Oxazolinone derivatives having cytosolic phospholipase A2 inhibitory activity

ABSTRACT

The present invention relates to a compound represented by the formula: ##STR1## wherein a and b are each a carbon atom; a bond: 
     - - - - - 
     between a and b indicates that it is a single bond or a double bond; 
     X is a hydrogen atom, an optionally substituted aryl group, an optionally substitued heteroaryl group, or an optionally substituted aralkyl group; 
     Y is a hydrogen atom, an optionally substituted aryl group, an optionally substituted aralkyl group, or a carboxyl group or related functional groups thereof; and 
     Z is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aralkyl, an optionally substituted arylalkenyl group, an optionally substituted heteroarylalkyl group, an optionally substituted heteroarylalkenyl group, an optionally substituted aryloxyalkyl group, an optionally substituted aralkyloxyalkyl group, an optionally substituted arylcarbonylalkyl group, an optionally substituted arylsulfonylalkyl group, an optionally substituted heteroarylsulfonylalkyl group, an optionally substituted aminoalkyl group, an optionally substituted carboxyalkyl group or related functional groups thereof, an optionally substituted alkyloxycarbonyl group, an optionally substituted aralkyloxycarbonyl group, an optionally substituted arylcarbonyl group, an optionally substituted alkylsulfonyl group, an optionally substituted arylsulfonyl group, or an optionally substituted heteroarylsulfonyl group; provided that X, Y and Z are not a hydrogen atom at the same time, and a pharmaceutical composition containing the same. The compounds of the present invention have a cytosolic phospholipase A 2  inhibitiory activity.

This application is a continuation of now abandoned application Ser. No.08/454,382, filed Jun. 15, 1995, which is a 371 of PCT/JP94/01716, filedOct. 13, 1994.

INDUSTRIAL UTILIZATION FIELD

The present invention relates to oxazolinone derivatives having acytosolic phospholipase A₂ inhibitory activity, and cytosolicphospholipase A₂ inhibitors containing the oxazolinone derivatives. Moreparticularly, it relates to oxazolin-2-one and oxazolidin-2-onederivatives having the activity, and cytosolic phospholipase A₂inhibitors containing the derivatives.

BACKGROUND OF THE INVENTION

Phospholipase A₂ (PLA₂) is a protein which hydrolyzes a 2-acyl esterbond of phospholipids, and examples thereof include cytosolic PLA₂ andsecretory PLA₂ which can be clearly distinguished from each other. Ithas been known that the cytosolic PLA₂ (cPLA₂) selectively hydrolyzesphospholipids containing arachidonic acid of which 2-position isesterified.

PRIOR ART AND PROBLEMS TO BE SOLVED BY THE INVENTION

Various oxazolinone derivatives have already been disclosed, and theyare described as having a central muscular relaxant action or aphospholipase A₂ inhibitory action Japanese Patent Publication (kokai)No. 61-286375, U.S. Pat. No. 5,071,988 and Japanese Patent Publication(koukoku) No. 52-10874!.

However, any of the publications mentioned above does not decribe aboutthe cytosolic PLA₂ and they don't even suggest oxazolinone derivativeshaving cytosolic PLA₂ inhibitory action.

Heretofore, the cytosolic PLA₂ has never been purified in high purity,and therefore, the PLA₂ inhibitiory action of the oxazolione derivativeshas never been reported.

The present inventors have paid attention to an interesting activity ofcPLA₂, and have developed a substance useful for treating inflammatorydiseases by inhibiting the activity. Since the compounds of the presentinvention inhibit the action of cPLA₂, the liberation of arachidonicacid from the phospholipid is prevented, thereby inhibiting theformation of various prostaglandins, leukotrienes, etc., which arereferred to as "arachidonic acid cascade". Accordingly, it is expectedthat the compounds of the present invention decrease the action oftransmitter substances of inflammation.

MEANS OF SOLVING THE PROBLEMS

The present invention relates to a compound represented by the formula:##STR2## wherein a and b are each indicate a carbon atom; a bond:

- - - - -

between a and b indicates that it is a single bond or a double bond;

X is a hydrogen atom, an optionally substituted aryl group, anoptionally substitued heteroaryl group, or an optionally substitutedaralkyl group;

Y is a hydrogen atom, an optionally substituted aryl group, anoptionally substituted aralkyl group, or a carboxyl group or relatedfunctional groups thereof; and

Z is a hydrogen atom, an optionally substituted alkyl group, anoptionally substituted alkenyl group, an optionally substituted alkynylgroup, an optionally substituted aralkyl, an optionally substitutedarylalkenyl group, an optionally substituted heteroarylalkyl group, anoptionally substituted heteroarylalkenyl group, an optionallysubstituted aryloxyalkyl group, an optionally substitutedaralkyloxyalkyl group, an optionally substituted arylcarbonylalkylgroup, an optionally substituted arylsulfonylalkyl group, an optionallysubstituted heteroarylsulfonylalkyl group, an optionally substitutedaminoalkyl group, an optionally substituted carboxyalkyl group orrelated functional groups thereof, an optionally substitutedalkyloxycarbonyl group, an optionally substituted aralkyloxycarbonylgroup, an optionally substituted arylcarbonyl group, an optionallysubstituted alkylsulfonyl group, an optionally substituted arylsulfonylgroup, or an optionally substituted heteroarylsulfonyl group; providedthat X, Y and Z are not a hydrogen atom at the same time.

However, the compounds represented by the following formulas areexcluded from the present invention. ##STR3##

In the compounds represented by the above formulas wherein the bondbetween a and b is a single bond, stereoisomers may exist, and alloptically active substances and a mixture thereof are included in thecompounds of the present invention.

The compounds of the present invention can be classified into thefollowing categories:

1) compounds wherein X and Y independently are an optionally substitutedphenyl or thienyl group, and

Z is an optionally substituted aralkyl group, an optionally substitutedheteroarylakyl group, an optionally substituted aryloxyalkyl group, anoptionally substituted aralkyloxyalkyl group, an optionally substitutedarylcarbonylalkyl group, or an optionally substituted arylsulfonyl groupprovided that Z is not benzyl or phenethyl;

2) compounds wherein X and Y independently are an optionallysubstituented phenyl group, and

Z is an optionally substituted alkyl group, an optionally substitutedalkenyl group or an optionally substituted alkynyl group provided that Zis not methyl;

3) compounds wherein the bond between a and b is a double bond, and

X and Y independently are an optionally substituted phenyl group; Z is agroup represented by the formula:

    --(CH.sub.2).sub.n NR.sup.1 R.sup.2

wherein n is 1, 2, or 3; and R¹ and R² are the same or different and area C₁ -C₄ alkyl group, or a group of the formula: ##STR4## wherein R⁴ isa C₁ -C₄ alkyl group or an optionally substituted phenyl group, or agroup of the formula:

    --(CH.sub.2).sub.n N.sup.+ R.sup.1 R.sup.2 R.sup.3 X.sup.-

wherein n is 1 or 2; R¹ and R² are as defined above; R³ is a C₁ -C₄alkyl; and X is a halogen atom;

4) compounds wherein the bond between a and b is a double bond,

X is a phenyl group optionally substituted with a sulfonylhydrazidegroup, a sulfonamide group, a phenyl group or --SO₃ H,

Y is a phenyl group, and

Z is a hydrogen atom; provided that X is not a phenyl group substitutedwith --SO₂ NH₂ ;

5) compounds wherein the bond between a and b is a double bond,

X and Y are the same and are a phenyl group substituted with a carboxylgroup or related functional group or groups, and

Z is a hydrogen atom provided that X and Y are not a phenyl groupsubstituted with --COCl;

6) compounds wherein the bond between a and b is a double bond,

X is a phenyl group;

Y is a phenyl group substituted with a phenyl group, and

Z is a hydrogen atom;

7) compounds wherein the bond between a and b is a double bond,

X is an optionally substituted phenyl group or an optionally substitutedaralkyl group,

Y is a hydrogen atom, and

Z is a hydrogen atom, an optionally substituted alkyl group, anoptionally substituted alkenyl group or an optionally substitutedalkynyl group, provided that when X is phenyl, Z is not a hydrogen atom;

8) compounds wherein the bond between a and b is a double bond,

X is an optionally substituted phenyl group or an aralkyl group,

Y is a hydrogen atom, and

Z is an optionally substituted aralkyl group, an optionally substitutedheteroarylalkyl group, an optionally substituted aryloxyalkyl group oran optionally substituted aralkyloxycarbonyl group;

9) compounds wherein the bond between a and b is a double bond,

X is a phenyl group,

Y is a carboxyl group or related functional groups thereof, and

Z is a hydrogen atom or an optionally substituted aralkyl group,provided that when Y is --COOCH₃, Z is a not hydrogen atom;

10) compounds wherein the bond between a and b is a single bond, and

X is a hydrogen atom; especially, compounds wherein the bond between aand b is a single bond, and X is a hydrogen atom, and Y is an optionallysubstituted aralkyl group, and Z is an optionally substituted alkenylgroup.

In the above formulas, examples of the "aryl group" in the "optionallysubstituted aryl group" include phenyl, naphthyl and the like. Amongthem, phenyl is preferred. The term "aralkyl group" in the "optionallysubstituted aralkyl group" means that optionally branched C₁ -C₆ alkylgroups which are substituted with aryl group(s), and examples thereofinclude benzyl, phenethyl, phenylpropylphenylbutyl, (α- or β-)naphthylmethyl and the like. Among them, benzyl is preferred. The term"heteroaryl group" in the "optionally substituted heteroaryl group"means 5- or 6-membered heterocycles having aromaticity, which containsat least one nitrogen, oxygen and/or sulfur in the ring. These may becondensed with a benzene ring. Examples thereof include thienyl, furyl,pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, quinolyl,isoxazolyl and the like. Among them, thienyl is preferred. Examples ofthe "substituent" in the "optionally substituted aralkyl group" or"optionally substituted heteroaryl group" include alkyl, alkoxy,halogen, phenyl and the like, and one or more substituents as mentionedabove can be substituted on the groups.

Examples of the "carboxyl group or related functional groups thereof" inY include groups represented by the formulas: ##STR5## Among them,preferred groups are those represented by the formulas: --COOH,--COOCH₃, and ##STR6##

The "optionally substituted aryl group" and "aralkyl group" in Y are asdefined in X, and preferred examples of Y include a hydrogen atom or aphenyl group.

Examples of the "substituent" in the "optionally substituted aryl group"include a sulfonylhydrazide group, sulfonamide group, carboxyl group orrelated functional groups thereof, halogen, alkyl, alkoxy, aryl, SO₃ H,SO₂ Cl, SO₂ O(CH₂)₃ Br and the like.

Examples of the "sulfonylhydrazide group" include the groups representedby the formulas: ##STR7## Among them, preferred group is thatrepresented by the formula: ##STR8##

Examples of the "sulfonamide group" include sulfonamides containingamino derivatives such as ammonia, pyrrolidine, piperidine, piperazine,morpholine, N-methylpiperazine, N-aralkylpiperazine,N-alkylsulfonylpiperazine, N-arylsulfonylpiperazine,piperidylalkylamine, piperazylalkylamine, morpholylalkylamine,N-alkylpiperidylamine, N-aralkylpiperidylamine, pyridiniumalkylamine,carboxyphenylamine, carbamoylphenylamine, bromoalkylamine and the like.Preferred "sulfonamide groups" are groups represented by the formulas:##STR9## More preferred group is a group represented by the formula:##STR10##

Examples of the carboxyl group or a related functional group thereofinclude groups represented by the formulas: ##STR11## Among them,preferred group is a carboxyl group.

"Halogen" means a group such as fluorine, chlorine, bromine and thelike.

"Alkyl" means a straight-chain or branched C₁ -C₆ alkyl, and examplesthereof include methyl, ethyl, propyl and the like.

"Alkoxy" means a straight-chain or branched C₁ -C₆ alkoxy, and examplesthereof include methoxy, ethoxy, propoxy, butoxy, bromobutoxy and thelike.

Examples of the "aryl group" include phenyl, naphthyl and the like,

In the definition of Z, the "alkyl group" in the "optionally substitutedalkyl group" means a straight-chain or branched C₁ -C₆ alkyl, andexamples thereof include methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, n-pentyl, i-pentyl, n-hexyl, neohexyl and the like.

The "alkenyl group" in the "optionally substituted alkenyl group" meansa straight-chain or branched C₂ -C₁₅ alkenyl, and examples thereofinclude vinyl, allyl, propenyl, butenyl, pentenyl, prenyl, geranyl,flunesyl, neryl, 3,7-dimethylocten-6-yl and the like. The "alkynylgroup" means a straight-chain or branched C₂ -C₇ alkynyl, and examplesthereof include ethynyl, 1- and 2-propynyl, 1-, 2- and 3-butynyl and thelike. The "aralkyl group" in the "optionally substituted aralkyl group"is as defined in the X, and preferred aralkyl group is a benzyl.

Examples of the "optionally substituted aminoalkyl group" include groupsrepresented by the formulas: ##STR12## Examples of the "optionallysubstituted carboxyalkyl group or related functional groups thereof"include --CH₂ COOH, --CH₂ COOCH(C₆ H₅)₂, --(CH₂)₂ COOCH(C₆ H₅)₂ and thelike. Examples of the "optionally substituted alkyloxycarbonyl group"include --COOtBu and the like. Examples of the "optionally substitutedaralkyloxycarbonyl group" include groups represented by the formulas:##STR13## Examples of the "optionally substituted arylcarbonyl group"include groups represented by the formulas: ##STR14## and the like.

The "alkylsulfonyl group" in the "optionally substituted alkylsulfonylgroup" means a C₁ -C₆ alkylsulfonyl group, and examples thereof includemethylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl,pentylsulfonyl, hexylsulfonyl and the like. Examples of the"arylsulfonyl group" in the "optionally substituted arylsulfonyl group"include phenylsulfonyl, α- and β-naphthylsulfonyl and the like. Examplesof the "heteroarylsulfonyl group" in the "optionally substitutedheteroarylsulfonyl group" include thienylsulfonyl, furylsulfonyl,pyrrolylsulfonyl, imidazolylsulfonyl, pyrazolylsulfonyl,pyridylsulfonyl, pyrimidinylsulfonyl, quinolylsulfonyl,isoxazolylsulfonyl and the like.

Examples of the "substituent" in the "optionally substituted alkylgroup", "optionally substituted alkenyl group", "optionally substitutedalkynyl group" and "optionally substituted aralkyl group" include C₁ -C₄alkyl group , C₃ -C₆ cycloalkyl group, C₁ -C₃ alkoxy group,methoxycarbonyl group, phenyl group, halogen atom, carboxyl group, nitrogroup and the like, and one or more substituents can be substitutedthereon.

The heteroaryl moiety, aryl moiety and aralkyl moiety in the "optionallysubstituted arylalkenyl group", "optionally substituted heteroarylalkylgroup", "optionally substituted heteroarylalkenyl group", "optionallysubstituted aryloxyalkyl group", "optionally substituted aralkyloxyalkylgroup", "optionally substituted arylcarbonylalkyl group", "optionallysubstituted arylsulfonylalkyl group", and "optionally substitutedheteroarylsulfonylalkyl group" are as defined in X. The alkenyl moietyand alkyl moiety thereof are as defined in Z. Examples ofthe"substituent" as mentioned above include one or more substituentsselected from alkyl, alkoxy, halogen, phenyl, trifluoromethyl and thelike.

The compounds of the present invention can be synthesized according to aconventional method. Hereinafter, a general synthetic method of thecompounds of the invention will be explained.

I. Oxazolinone derivatives ##STR15##

1) Bond between a and b: double bond (oxazolin-2-one derivatives) 1)-iX═Y=aryl group or aralkyl group

The compounds of the present invention can be mainly synthesizedaccording to any one of the methods described in the publishedliteratures G. H. Hakimelahi, C. B. Boyce and H. S. Kasmai, HelveticaChim. Acta 60, 342 (1977)!. ##STR16##

That is, a bezoin compound B and a carbamate ester are heated in thepresence of a base or an acid to give the objective product C. X and Ymay be an aryl group or an aralkyl group other than a benzene ring, andthe ester residue of carbamic acid may be an alkyl, aryl and aralkylgroup, such as methyl, ethyl, propyl, phenyl, benzyl and the like. Theacid to be used as a catalyst may be an acid such as hydrochloric acid,sulfuric acid, polyphosphoric acid, toluenesulfonic acid, phosphoricacid and the like. As the basic catalyst, there can be used pyridine,triethylamine, 4,4-dimethylaminopyridine, N,N-diisopropylethylamine,1,5-diazabicyclo 4.3.0!non-5-ene (DBN), 1,4-diazabicyclo 2.2.2!octane(DABCO), 1,8-diazabicyclo 5.4.0!undece-7-ene (DBU), potassium carbonate,sodium carbonate, potassium hydroxide, sodium hydroxide and the like.

This reaction can be normally completed by heating the reaction mixtureat 60° C.˜200° C., preferably at 100° C.˜180° C., for 1 hour˜48 hours,preferably for 8 hours˜30 hours. As the solvent, there can be usedN,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO) and the like, butthe objective product can be obtained in good yield in the absence ofthe solvent.

1)-ii X≠Y: X, Y═aryl group or aralkyl group ##STR17## In the reactionscheme, only chlorosulfonylation is shown, but acylation, alkylation,chlorocarbonylation, halogenation, nitration, etc. can occur, similarly.

Regarding 5-(4'-sulfonylphenyl) derivative, 4,5-diaryloxazolin-2-one Cobtained in the above method 1)-i) is reacted with chlorosulfonic acidto form a 5-chlorosulfonylaryl derivative D which is then reacted withvarious amines to give a sulfonamide derivative E. NOE determination on¹ H NMR using a chlorosulfonyl derivative D has revealed that thechlorosulfonation occurs on the aromatic ring X but does not occure on Yin this reaction.

The chlorosulfonation can be accomplished by reacting at 0° C.˜100° C.,preferably at 20° C.˜60° C., for 1 hour˜6 hours in the presence of asolvent such as CHCl₃, CH₂ Cl₂ and the like. Examples of amines whichlead to the sulfonamide derivatives include ammonia, pyrrolidine,piperidine, piperazine, morpholine, N-methylpiperazine,piperidylalkylamine, morpholylalkylamine, N-alkylpiperidineamine,N-aralkylpiperidylamine, pyridiniumalkylamine, carboxyphenylamine,carbamoylphenylamine, hydrazine, 1-aminopyrrolidine, 1-aminopiperidine,4-amino-1,2,4-triazole, 1-amino-4-methylpiperazine, 4-aminomorpholine,1,4-diaminopiperadine, and amino or hydrazine derivatives which aregenerally used.

In addition to these sulfonamide compounds, oxazolin-2-one derivativeswherein X≠Y (X and Y respectively indicate an aryl group or aralkylgroup) can be obtained by a method described in the published literatureB. Zwanenburg et al., J. Org. Chem., 49, 2231 (1984)!. ##STR18##

That is, an aldehyde derivative and an α-bromo ester derivative aresubjected to the Darzen's reaction in the presence of a base such assodium alkoxide, lithium diisopropylamide, etc. and the resultingepoxide is hydrolyzed to give carboxylic acid F. This carboxylic acid isactivated by leading to acid chloride or active ester, using thienylchloride, phosphoryl chloride, phosphorous pentachloride,alkylchloroformate, oxalyl chloride, carbodiimide derivative,N-hydroxysuccinimide derivative, N-hydroxybenzotriazole derivative andthe like. Then, it was converted into a carbonylazide derivative G withsodium azide or trimethylsilyl azide, and the carbonylazide derivativeis subjected to the rearrangement-ring opening reaction with heating togive an oxazolin-2-one derivative H as the objective product. 1)-iii)X≠Y: X=aryl group, Y=carboxylic acid residue

Oxazolin-2-ones containing a carboxyl group or related functional groupsat the 4-position can be synthesized by a method of C-g. Shin et al.Chem. Lett, 1171 (1982)!. ##STR19##

That is, α-dehydroamino acid I obtained from a pyruvic acid derivativeand carbamates is reacted with acetyl chloride or thionyl chloride togive a cyclic anhydride J. The resulting cyclic anhydride is reactedwith a halogenating agent such as N-bromosuccininide (NBS),N-chlorosuccinimide (NCl), etc. in an alcohol solvent such as methanoletc. to give a product K which is converted, using an organic base (e.g.pyridine, triethylamine, N,N-dimethylaminopyridine (DMAP), DBN, DABCO,DBU, etc.) or an inorganic base (e.g. potassium carbonate, sodiumcarbonate, potassium hydroxide, sodium hydroxide, etc.), to give theobjective compound L. In the above structural formulas, Y is acarboxylate group such as methyl ester, etc. Another compound of thepresent invention can be produced by hydrolyzing the resulting compoundL to convert into carboxylic acid derivatives such as various amides.

2) Bond between a and b: single bond (oxazolidin-2-one derivative)

The synthesis of the compounds of the present invention can beaccomplished by cyclization of various 2-amino alcohol derivatives andconverting the same to oxazolidin-2-ones using suitable reagents orreactions. It is apparent that two (when X or Y is a hydrogen atom) orfour optically active substances of oxazolidin-2-ones can be synthesizedstereoselectively by selecting optically active 2-amino alcohols. Theseoptically active 2-amino alcohols can be synthesized by applying themethod of S. D. Burke et al. (Tetr. Lett., 28, No. 34, 3105, 1987),which comprises synthesizing a mono-protected vicinal-glycols fromoptically active α-alkoxy esters, to the amino acid esters. ##STR20##

In this reaction, an ester is firstly reduced to give an aldehydeintermediate which is then subjected to Grignard reaction in one potwithout isolating it. In this case, the aldehyde as the intermediateforms a chelation by a reducing agents-derived metal, and thestereochemistry of the following Grignard reaction is controlled by astructural specificity of this chelation. Accordingly, thestereochemistry of 2-amino ethanols as the product can be controlled bythe nature of a metal hydride as the reducing agent. Examples of thereducing agent include lithium borohydride, lithium tri-tert-butoxyaluminum hydride, diisobutyl aluminum hydride, etc., and metal hydrideswhich are normally used for reducing esters to aldehydes. As theGrignard reagent, there can be used any one which can introduce asubstituent X (XM halogen) at the 5-position of oxazolin-2-ones in thefollowing process, and typical examples thereof include phenylmagnesiumbromide and the like. As the reaction solvent, there can be used ethersolvents such as ether, tetrahydrofuran, dimethoxyethane and the like,and the reaction is normally conducted at -100° C.˜40° C., preferably at-78° C.˜0° C.

Some of these 2-amino alcohols are commercially available and can beused as a synthetic starting material for oxazolidin-2-ones of thepresent invention.

Then, the ring-closure will be conducted to convert 2-amino alcoholsinto oxazolidin-2-ones. Almost all of cases, they are subjected to thering-closure in a solvent (e.g. ether, tetrahydrofuran, methylenechloride, benzene, toluene, etc.) at 0° C.˜30° C. in the presence of abase which is normally used (e.g. triethylamine, pyridine, etc.), usingphosgene or its stable derivative thereof, e.g. triphosgene. ##STR21##

Among 2-amino alcohols, a compound N' which is protected with acarbamate type amino protective group such as a carbobenzoxy group canbe converted into oxazolidin-2-ones by subjecting it to the ring-closureunder a basic condition according to the method of S. Kano et al. Tetr.Left., 28, No. 50, 6331 (1987)!. ##STR22##

They are reacted in tetrahydrofuran, water, methanol or a suitable mixedsolvent thereof at 0° C.˜30° C., using metal hydroxides (e.g. NaOH, KOH,etc.) or organic bases which are normally used (e.g. triethylamine, DBU,etc.) as a base.

II. N-substituted oxazolinone derivative

II-1) The N-substitution reaction is conducted using oxazolin-2-onesthus obtained as described above or oxazolidin-2-ones according to themethod described in the published literature G. H. Hakimelahi et al.,Helv. Chim. Acta, 60, 342 (1977)!. ##STR23##

That is, an oxazolin-2-one derivative A is reacted with various halidessuch as alkyl halide, alkenyl halide, alkynyl halide, aralkyl halide,alkyloxycarbonyl halide, aralkyloxycarbonyl halide, arylcarbonyl halide,alkylsulfony halide, arylsulfonyl halide, etc. in the presence of astrong base such as sodium hydride, n-butyllithium, potassium hydride,potassium t-butoxide, lithium diisopropylamide, sodium amide, etc. togive the objective product Q. Examples of the solvent includetetrahydrofuran, diethyl ether, dioxane, benzene, toluene,dimethylformamide (DMF), dimethylacetamide (DMA), dimethoxyethane,dimethyl sulfoxide (DMSO) and the like. This reaction is conducted at-78° C.˜100° C., preferably at -20° C.˜60° C.

II-2) N-substituted oxazolin-2-ones can also be synthesized by a methodof introducing an amino compound using a cyclic carbonate R as astarting material J. C. Sheehan et al., J. Org. Chem., 38, No.17, 3034(1973)!, in addition to the N-substitution reaction described in theabove item (1). ##STR24##

A benzoin derivative and cyclic carbonate R synthesized from phosgeneare reacted with various amines, then with trifluoroacetic acid (TFA) togive oxazolin-2-ones S. The reaction between carbonate and amine isgenerally conducted at about room temperature in DMF. The resultingunstable intermediate is also converted into oxazolin-2-one S at roomtemperature in TFA. According to this method, a compound, which can notbe easily prepared by the reaction between oxazolin-2-ones and halidesas described in the item II-1), can be easily synthesized.

III. Ammonium derivatives

Quaternary salts are synthesized by a normal method, for example, byreacting halides as a starting material with amines or reacting aminesas a starting material with alkyl halides. As the solvent, there can beused methanol, ethanol, tetrahydrofuran, methylene chloride, diethylether, etc., and the reaction is normally conducted within a range fromabout room temperature to about 100° C.

Further, the present invention relates to a phospholipase A₂ inhibitorcontaining a compound represented by the formula: ##STR25## wherein aand b are each a carbon atom; a bond:

- - - - -

between a and b indicates that it is a single bond or a double bond;

X is a hydrogen atom, an optionally substituted aryl group, anoptionally substitued heteroaryl group, or an optionally substitutedaralkyl group;

Y is a hydrogen atom, an optionally substituted aryl group, anoptionally substituted aralkyl group, or a carboxyl group or relatedfunctional groups thereof; and

Z is a hydrogen atom, an optionally substituted alkyl group, anoptionally substituted alkenyl group, an optionally substituted alkynylgroup, an optionally substituted aralkyl, an optionally substitutedarylalkenyl group, an optionally substituted heteroarylalkyl group, anoptionally substituted heteroarylalkenyl group, an optionallysubstituted aryloxyalkyl group, an optionally substitutedaralkyloxyalkyl group, an optionally substituted arylcarbonylalkylgroup, an optionally substituted arysulfonylalkyl group, an optionallysubstituted heteroarylsulfonylalkyl group, an optionally substitutedaminoalkyl group, an optionally substituted carboxyalkyl group orrelated functional groups thereof, an optionally substitutedalkyloxycarbonyl group, an optionally substituted aralkyloxycarbonylgroup, an optionally substituted arylcarbonyl group, an optionallysubstituted alkylsulfonyl group, an optionally substituted arylsulfonylgroup, or an optionally substituted heteroarylsulfonyl group; providedthat X, Y and Z are not a hydrogen atom at the same time; together withand a pharmaceutically acceptable carrier.

It will be understood that pharmaceutical compositions of the presentinvention also include pharmaceutical compositions containing knowncompounds represented by the following formulas: ##STR26## Theexperiments carried out by the present inventors have revealed, for thefirst time, that these known compounds also have a cytosolic PLA₂inhibitory activity.

The production process of the known compound 0003 will be explained inReference Example 1 described hereinafter. Further, the known compounds0001 and 0002 can be easily produced according to the process ofReference Example 1.

The pharmaceutical compositions of the present invention can be orallyor parenterally administered, and therefore, they can be formulated inthe form such as oral preparations, injections, ointments and the like.

The dose of the compounds of the present invention varies depending uponthe objective therapeutic effect, administration route, patient's ageand weight, severity of diseases and the like. The daily dose isgenerally 50 mg˜1000 mg and is generally administered 2 to 5 times perday. Accordingly, the pharmaceutical compositions of the presentinvention can be formulated in an unit dosage form containing thedivided dose.

The following Examples to produce the compounds of the present inventionas well as Reference Examples further illustrate the present inventionin detail. However, they are not to be construed to limit the scope ofthe present invention.

The abbreviations used in Examples and Reference Examples have thefollowing meanings. "Nujol" is nujol, "neat" is thin layer, "base peak"is base peak, "MeOH" is methanol, ""EtOH" is ethanol, "EtOAc" or "AcOEt"is ethyl acetate, "DMSO" is dimethyl sulfoxide, "DMF" isN,N'-dimethylformamide, "THF" is tetrahydrofuran, "eq" is equivalent and"Ph" is phenyl group, respectively.

EXAMPLE 1 Synthesis of 5-4-(4-methyl)piperazinylsulfenyl!phenyl-4-phenyl-2-oxazolone (0037)##STR27##

(1) A mixture of benzoin (213 g, 1.0 mol), urethane (445 g, 5.0 mol) andpyridine (80 ml) was heated to 160° C. and dissolved, then stirred atthe same temperature for 18 hours. Ethanol produced by the reaction wasdistilled off under reduced pressure and, after pyridine (80 ml) wasadded again, the mixture was stirred at 160° C. for 22 hours. Water wasadded with ice cooling and the precipitate was filtered. The precipitatewas recrystallized from dichloromethane-methanol to give 176 g of YI1(yield 79.6%).

Melting point: 203.5°-207.8° C.

¹ H NMR (CDCl₃): 7.28-7.41 (m, 5H), 7.42-7.53 (m, 5H)

IR (KBr): 690, 748, 755, 950, 978, 1022, 1058, 1448, 1503, 1602, 1752,3040, 3430 (cm⁻¹)

Elemental analysis Calcd. (%) C: 75.94, H: 4.67, N: 5.90 Found (%) C:75.76, H: 4.76, N: 5.91

(2) YI1 (0.50 g, 2.1 mmol) obtained above was dissolved in chloroform(20 ml) and chlorosulfonic acid (0.42 ml, 6.3 mmol) was added at roomtemperature, and the mixture was stirred under reflux for 10 minutes.Methyl ethyl ketone and brine were added and the mixture was partitionedbetween them. The organic layer was washed twice with water and dried,followed by washing in turn with a small amount of dichloromethane,water and methanol to give 0.18 g of YI2 (yield 26%).

Melting point: 232.5°-234.0° C.

¹ H NMR (d⁶ DMSO): 7.33 (d, 2H, J=8Hz), 7.41-7.53 (m, 5H), 7.56 (d, 2H,J=8 Hz)

IR (Nujor): 560, 596, 730, 756, 840, 1056, 1162, 1175, 1194, 1409, 1430,1590, 1746, 3090, 3180 (cm³¹ 1)

Elemental analysis: C₁₅ H₁₀ ClNO₄ S.0.2H₂ O.0.1HCl Calcd. (%) C: 52.52,H: 3.09, Cl: 11.37, N: 4.08, S: 9.35 Found (%) C: 52.15, H: 3.12, Cl:11.70, N: 4.09, S: 9.05

(3) YI2 (200 mg, 0.60 mmol) obtained above was dissolved intetrahydrofuran (20 ml) and N-methylpiperazine (0.08 ml, 0.72 mmol) wasadded under ice cooling, and the mixture was stirred at 0° C. for 4hours. The solvent was distilled off and the residue was recrystallizedfrom dichloromethane-tetrahydrofuran to give 129 mg of the titledcompound 0037 (yield 54%).

Melting point: 270.0°-271.0 ° C.

¹ H NMR (d⁶ DMSO): 2.13 (s, 3H), 2.33 (m, 4H), 2.88 (m, 4H), 7.54 (m,5H), 7.56 (d, 2H, J=9 Hz), 7.68 (d, 2H, J=9 Hz)

IR (Nujor): 590, 612, 704, 720, 743, 755, 778, 952, 1051, 1101, 1150,1159, 1172, 1286, 1333, 1595, 1758, 2660, 2720 cm⁻¹

Elemental analysis: C₂₀ H₂₁ N₃ O₄ S.0.4H₂ O Calcd. (%) C: 59.07, H:5.40, N: 10.33, S: 7.88 Found (%) C: 59.24, H: 5.50, N: 10.21, S: 7.50

EXAMPLES 2 TO 14

According to the method similar to that described in Example 1, thereaction was conducted to give the compounds listed in the followingtable.

                                      TABLE 1                                     __________________________________________________________________________     ##STR28##                                                                                             Melting                                              Example No.                                                                         Substituent X:     point IR (cm.sup.-1)                                 __________________________________________________________________________    2     SO.sub.2 NHNH.sub.2                                                                              dp.   (Nujol) 567, 602, 747,                         (0008)                   155-  839, 1023, 1058, 1171,                                                  178° C.                                                                      1336, 1601, 1737,                                                             3150, 3290, 3380,                                                             3560                                           3 (0013)                                                                             ##STR29##         mp. 241-243° C.                                                              (Nujol) 594, 610, 748, 922, 937, 1169,                                        1320, 1345, 1598, 1765, 2720, 3340             4 (0014)                                                                             ##STR30##         dp. 185-195° C.                                                              (Nujol) 556, 609, 693, 732, 751, 1054,                                        1162, 1599, 1750, 2650, 3200                   5 (0015)                                                                             ##STR31##         dp. 240-243° C.                                                              (Nujol) 556, 628, 739, 755, 1055, 1170,                                       1596, 1752, 3080                               6 (0016)                                                                             ##STR32##         dp. 180-188° C.                                                              (Nujol) 570, 598, 732, 754, 830, 1055,                                        1163, 1280, 1380, 1600, 1755, 3150             7 (0017)                                                                             ##STR33##         dp. 180-194° C.                                                              (Nujol) 512, 609, 770, 1050, 1102, 1161,                                      1319, 1592, 1658, 3400                         8 (0035)                                                                             ##STR34##         mp. 259-262° C.                                                              (Nujol) 561, 629, 696, 736, 752, 1070,                                        1157, 1597, 1750, 3260                         __________________________________________________________________________

                                      TABLE 2                                     __________________________________________________________________________                         Melting                                                  Example No.                                                                         Substituent X: point IR (cm.sup.-1)                                     __________________________________________________________________________    9 (0036)                                                                             ##STR35##     dp. 210-217° C.                                                              (Nujol) 560, 625, 735, 755, 839, 859, 1055,                                   1100, 1163, 1600, 1749, 3170                       10 (0038)                                                                            ##STR36##     mp. 104-131° C.                                                              (Nujol) 603, 735, 778, 927, 1114, 1158, 1600,                                 1780, 3110, 3630                                   11 (0063)                                                                            ##STR37##     dp. 257-287° C.                                                              (Nujol) 567, 599, 757, 910, 1164, 1377, 1600,                                 1733, 3150, 3380                                   12 (0064)                                                                            ##STR38##     mp. 248-250° C.                                                              (Nujol) 579, 597, 745, 925, 1056, 1158, 1598,                                 1752, 3090                                         13 (0074)                                                                            ##STR39##     300° C.<                                                                     (Nujol) 558, 596, 698, 732, 906, 1152, 1245,                                  1607, 1730, 3180                                   14 (0010)                                                                           SO.sub.3 H     300° C.<                                                                     (Nujol) 570, 635, 738, 1009, 1046, 1130, 1202,                                1220, 1603, 1770, 3150, 3280                       __________________________________________________________________________

EXAMPLES 15 TO 18 ##STR40## EXAMPLE 15

Compound (0067) wherein R is 2-naphthalenesulfonyl

Sodium hydride (100 mg, about 2.5 mmol) washed with a small amount ofn-hexane was suspended in benzene (2 ml) and YI1 (200 mg, 0.84 mmol)produced in Example 1 (1) was added to the suspension at roomtemperature, and the mixture was stirred for 20 minutes.2-Naphthalenesulfonyl chloride (950 mg, 4.2 mmol) was dissolved inbenzene (3 ml) and the resulting solution was added thereto at roomtemperature, followed by stirring for one hour and half. Ethyl acetateand water were added and the mixture was partitioned between them. Then,the organic layer was dried and the resulting solid was recrystallizedfrom ethyl acetate/dichloromethane to give 152 mg of compound 0067(yield 42.2%).

Melting point: 205.5°-207.5° C.

¹ H NMR (CDCl₃): 7.06-7.24 (m, 5H), 7.36-7.76 (m, 7H), 7.81-8.04 (m,4H), 8.41 (d, 1H, J=2 Hz)

IR (Nujor): 543, 577, 653, 700, 750, 766, 770, 808, 1062, 1073, 1179,1230, 1250, 1385, 1790 (cm⁻¹) Elemental analysis (%): C₂₅ H₁₇ NO₄S.0.2H₂ O Calcd. (%) C: 69.66, H: 4.07, N: 3.25, S: 7.44 Found (%) C:69.56, H: 4.12, N: 3.26, S: 7.33

EXAMPLE 16

Compound (0071) wherein R is prenyl

According to the method similar to that described in Example 15, thereaction was conducted to give compound 0071.

Melting point: 91.0°-92.0° C.

¹ H NMR (CDCl₃): 1.31 (s, 3H), 1.61 (s, 3H), 4.08 (d, 2H, J=7 Hz), 5.07(t, 1H, J=7 Hz), 7.14-7.30 (m, 5H), 7.35-7.46 (m, 2H), 7.47-7.56 (m, 3H)

IR (Nujor): 696, 750, 762, 770, 1056, 1745 (cm⁻¹)

Elemental analysis: Calcd. (%) C: 78.66, H: 6.27, N: 4.59 Found (%) C:78.78, H: 6.43, N, 4.61

EXAMPLE 17

Compound (0070) wherein R is geranyl

According to the method similar to that described in Example 15, thereaction was conducted to give compound 0070.

Colorless liquid

¹ H NMR (CDCl₃): 1.29 (s, 3H), 1.57 (s, 3H), 1.66 (s, 3H), 1.85-2.10 (m,4H), 4.10 (d, 1H, J=7), 4.90-5.13 (m, 2H), 7.15-7.30 (m, 5H), 7.36-7.54(m, 5H)

Elemental analysis (%): C₂₅ H₂₇ NO₂.0.4H₂ O O Calcd. (%) C: 78.87, H:7.36, N: 3.68 Found (%) C: 78.74, H: 7.31, N, 3.76

EXAMPLE 18

Compound (0069) wherein R is farnesyl

According to the method similar to that described in Example 15, thereaction was conducted to give compound 0069.

Colorless liquid

¹ H NMR (CDCl₃): 1.30 (s, 3H), 1.52-1.63 (m, 9H), 1.67 (s, 3H),1.81-2.17 (m, 12H), 4.09 (d, 2H, J=7), 4.96-5.16 (m, 4H), 7.14-7.30 (m,5H), 7.35-7.55 (m, 5H)

Rf value: 0.2 (ethyl acetate/n-hexane=1/6)

EXAMPLES 19 TO 26

According to the method similar to that described in Example 15, thereaction was conducted to give the compounds listed in the followingtable.

                  TABLE 3                                                         ______________________________________                                         ##STR41##                                                                                          Melting                                                 Example No.                                                                           Substituent: R                                                                              point    IR(cm.sup.-1)                                  ______________________________________                                        19                    mp.      (Nujol)562, 591, 677,                          (0066)                188-     700, 750, 1060,                                                      189° C.                                                                         1172, 1192,                                                                   1230, 1788                                     20      SO.sub.2 (CH.sub.2).sub.5 CH.sub.3                                                          mp.      (Nujol)555, 690, 700,                          (0068)                154-     752, 772, 1068,                                                      156° C.                                                                         1165, 1235,                                                                   1785                                           21      Geranyl geranyl                                                                             Liquid                                                  (0072)                                                                        22      CPh.sub.3     dp.      (Nujol)687, 695, 738,                          (0116)                156-     753, 1060,                                                           164° C.                                                                         1253, 1291,                                                                   1492, 1598,                                                                   1763                                           23      CHPh.sub.2    mp.      (Nujol)695, 731, 750,                          (0117)                195-     1064, 1258,                                                          202° C.                                                                         1335, 1761                                     ______________________________________                                    

                                      TABLE 4                                     __________________________________________________________________________     ##STR42##                                                                                               Melting                                            Example No.                                                                         Substituent          point                                                                              IR(cm.sup.-1)                                 __________________________________________________________________________    24 (0040)                                                                            ##STR43##           mp. 60- 70° C.                                                              (Nijol) 580, 597, 700, 741, 929, 1050,                                        1164, 1341, 1382, 1598, 1762                         ##STR44##                                                                     ##STR45##                                                              25 (0065)                                                                            ##STR46##           mp. 225- 223° C.                                                            (Nijol) 596, 611, 697, 750, 942, 1166,                                        1190, 1377, 1751, 2220, 3380, 3590                   ##STR47##                                                                     ##STR48##                                                              26 (0118)                                                                            ##STR49##           mp. 152- 179° C.                                                            (Nijol) 705, 742, 1100, 1149, 1212, 1411,                                     1609, 1649, 1745, 2430,                       __________________________________________________________________________                                    3075                                      

EXAMPLES 27 TO 28 ##STR50##

According to the method similar to that described in Example 15, thesynthesis was conducted using Y18 described in J. Org. Chem., 49, 2231(1984) as a starting material, and the following compounds wereobtained.

EXAMPLES 27

Compound (0095) wherein R¹ is geranyl

Melting point: 56.0°-56.5° C.

¹ H NMR (CDCl₃): 1.61 (s, 3H), 1.68 (s, 3H), 1.77 (s, 3H), 2.10 (brs,4H), 4.23 (d, 2H, J=7 Hz), 5.07 (m, 1H), 5.30 (t, 1H, J=7 Hz), 6.69 (s,1H), 7.22-7.51 (m, 5H)

IR (Nujor): 684, 733, 1020, 1040, 1182, 1731, 3130 (cm⁻)

Elemental analysis (%): C₁₉ H₂₃ NO₂.0.1H₂ O Calcd. (%) C: 76.27, H:7.82, N: 4.68 Found (%) C: 76.26, H: 7.63, N: 4.86

EXAMPLES 28

Compound (0097) wherein R¹ is benzhydryl

Melting point: 174°-183° C.

¹ H NMR (CDCl₃): 6.54 (s, 1H), 6.61 (s, 1H), 7.19-7.49 (m, 15H)

IR (Nujor): 681, 688, 717, 735, 750, 1085, 1166, 1213, 1370, 1492, 1750,3030, 3060 cm⁻¹

Elemental analysis (%): Calcd. (%) C: 80.71, H, 5.23, N, 4.28 Found (%)C: 81.03, H, 5.63, N: 4.03

EXAMPLES 29 TO 32

According to the method similar to that described in Example 27, thereaction was conducted to give the compounds listed in the followingtable.

                  TABLE 5                                                         ______________________________________                                         ##STR51##                                                                                           Melting                                                Exam-                  point                                                  ple No.                                                                             Substituent: R   ( )      IR(cm.sup.-1)                                 ______________________________________                                        29 (0094)                                                                            ##STR52##       88-89    (Nijol) 687, 740, 1023, 1042, 1180, 1383,                                     1400, 1738, 3135                              30 (0096)                                                                            ##STR53##       138-140  (Nijol) 688, 703, 745, 1018, 1180, 1398,                                      1440, 1745, 3130                              31    Tr               143-162  (Nijol) 702, 740,                             (0115)                          759, 1150, 1240,                                                              1496, 1775                                    32 (0119)                                                                            ##STR54##       149-152  (Nijol) 691, 744, 775, 1019, 1095, 1197,                                      1403, 1742, 3115                              ______________________________________                                    

EXAMPLES 33 TO 36 ##STR55## EXAMPLE 33

Compound 0142

(1) Diisopropylamine (2.79 ml, 19.9 mmol) was dissolved in THF (30 ml)and butyl lithium (12.4 ml, 19.9 mmol) was slowly added at -65° C., andthe mixture was stirred under ice cooling for 25 minutes. The LDAsolution prepared above was slowly added at -78° C. to a solution ofdiphenylacetaldehyde (3.00 g, 15.3 mmol), methyl bromoacetate (1.74 ml,18.4 mmol) in THF (30 ml). After stirring at -78° C. for 45 minutes, themixture was concentrated under reduced pressure and partitioned betweenethyl acetate and water. The organic layer was dried over magnesiumsulfate and concentrated under reduced pressure and the residue waspurified by silica gel column chromatography to give 2.68 g of yellowliquid YI12.

(2) YI12 (9.46 g, 36.2 mmol) obtained above was dissolved in methanol(200 ml), to which were added a 28 wt % NaOMe methanol solution (7.4 ml,36 mmol) and H₂ O (0.65 ml, 36 mmol) at room temperature, and themixture was allowed to stand overnight. The solvent was evaporated todryness to give 10.7 g of a white solid (YI13).

(3) YI13 (1.00 g, 3.6 mmol) obtained above was dissolved in THF (30 ml)and oxalyl chloride (1.1 ml, 13 mmol) and two drops of DMF were added inturn at -20° C., and the mixture was stirred at room temperature for onehour. The reaction mixture was concentrated under reduced pressure andflushed twice with THF. Then, THF (30 ml) and trimethylsilyl azide (2.4ml, 18 mmol) were added at room temperature and the mixture was refluxedat 85° C. for 3 hours. The reaction solution was concentrated underreduced pressure and partitioned between a dichloromethane solutioncontaining 10% methanol and water, and the organic layer was washed withwater and concentrated under reduced pressure. The residue was purifiedby silica gel column chromatography and recrystallized fromdichloromethane/ether to give 63 mg of compound 0142 (yield 4.6%).

Melting point: 196.0°-202.5° C.

¹ H NMR (CDCl₃): 5.16 (s, 1H), 6.02 (t, 1H, J=2 Hz), 7.16-7.38 (m, 10H)

IR (Nujor): 703, 736, 759, 800, 954, 1232, 1256, 1494, 1730, 1740, 3130,3150, 3200 (cm⁻¹)

Elemental analysis: Calcd. (%) C: 76.48, H: 5.21, N: 5.57

Found (%) C: 76.20, H: 5.39, N: 5.63

EXAMPLE 34

Compound (0153) wherein R² is 3-(p-trifluoromethylphenoxy)propyl

Compound 0142 (70 mg, 0.28 mmol) obtained in Example 33 was dissolved inDMF (2 ml) and about 60% sodium hydride (12 mg, 0.31 mmol) and3-(p-trifluoromethylphenoxy)propyl bromide (160 mg) were added at roomtemperature, and the mixture was stirred for 30 minutes. Ethyl acetateand water were added and the mixture was partitioned between them, andthe organic layer was washed with water and then concentrated underreduced pressure. The residue was purified by silica gel columnchromatography and recrystallized from ether/n-hexane to give 68 mg ofcompound 0153 (yield 54%).

Melting point:: 99.5°-101.5° C.

¹ H NMR (CDCl₃): 2.16 (m, 2H), 3.74 (t, 2H, J=7 Hz), 4.02 (t, 2H, J=6Hz), 5.12 (s, 1H), 5.90 (d, 1H, J=1Hz), 6.88 (d, 2H, J=9 Hz), 7.10-7.34(m, 10H), 7.52 (d, 2H, J=9 Hz)

IR (Nujor): 639, 702, 726, 739, 749, 842, 967, 1069, 1084, 1112, 1121,1155, 1165, 1178, 1262, 1315, 1321, 1330 ,1407, 1498, 1521, 1618, 1769,3035, 3070, 3150 (cm⁻¹)

Elemental analysis: Calcd. (%) C: 68.87, H: 4.89, F: 12.57, N: 3.09Found (%) C: 68.57, H: 5.05, F: 12.32, N: 3.06

EXAMPLE 35

Compound (0155) wherein R² is prenyl

The reaction is conducted in the manner similar to that described inExample 34.

Liquid (yellow)

¹ H NMR (CDCl₃): 1.73 (s, 3H), 1.74 (s, 03H), 4.09 (d, 2H, J=7), 5.14(s, 1H), 5.20 (t, 1H, J=7), 5.91 (d, 1H, J=1), 7.17-7.37 (m, 10H)

IR (film): 685, 702, 723, 745, 751, 965, 1025, 1066, 1070, 1146, 1161,1193, 1355, 1368, 1381, 1395, 1451, 1498, 1601, 1753, 2940, 2985, 3040(cm⁻¹)

Elemental analysis: C₂₁ H₂₁ NO₂.0.2H₂ O Calcd. (%) C: 78.09, H: 6.68, N:4.34 Found (%) C: 77.89, H: 7.01, N: 4.58

EXAMPLE 36

Compound (0156) wherein R² is geranyl

The reaction is conducted in the manner similar to that described inExample 34.

Yellow liquid

¹ H NMR: (CDCl₃) 1.57 (s, 3H), 1.65 (s, 3H), 1.67 (s, 3H), 2.04 (brs,4H), 4.12 (d, 2H, J=7), 5.03 (m, 1H), 5.14 (s, 1H), 5.20 (t, 1H, J=7),5.92 (d, 1H, J=1), 7.16-7.38 (m, 10H)

IR: (Nujor) 701, 717, 747, 965, 1083, 1094, 1160, 1378, 1405, 1437,1498, 1603, 1663, 1738, 3035, 3070, 3150 (cm⁻¹)

Elemental analysis: C₂₆ H₂₉ NO₂.0.1H₂ O Calcd. (%) C: 80.21, H: 7.56, N:3.60 Found (%) C: 80.27, H: 7.68, N: 3.46

EXAMPLES 37 TO 39

According to the method similar to that described in Example 34, thereaction was conducted to give the compounds listed in the followingtable.

                                      TABLE 6                                     __________________________________________________________________________                            Melting                                               Example No.                                                                         Substituent       point (°C.)                                                                 IR(cm.sup.-1)                                    __________________________________________________________________________    37 (0143)                                                                            ##STR56##        Liquid                                                                             (film) 697, 742, 965, 1065, 1080, 1152,                                       1396, 1451, 1495, 1754, 3040                     38    R.sup.2 = PMZ     179-180                                                                            (Nijol) 700, 747,                                (0154)                       1050, 1166, 1731,                                                             1229, 1250, 1270,                                                             1384, 1513, 1612,                                                             1825                                             39 (0157)                                                                            ##STR57##        127-129                                                                            (Nijol) 700, 710, 742, 825, 1053, 1139,                                       1410, 1492, 1770, 3130                           __________________________________________________________________________

Reference Example 1 ##STR58##

The compound YI1 (500 mg, 2.1 mmol) produced in Example 1 (1) andbenzhydryl bromoacetate (723 mg, 2.4 mmol) were dissolved in DMF (3 ml),and then NaH (60% in oil) (100 mg, 2.5 mmol) was added in severalportions under a N₂ stream with ice cooling. After the addition, themixture was warmed to room temperature and stirred for 2 hours. Thereaction solution was poured into ice water and extracted with AcOEt.The organic layer was washed in turn with water and brine, and thendried over Na₂ SO₄, and concentrated under reduced pressure to give 994mg of a light brown syrup-like substance. The substance was subjected tosilica gel column chromatography and eluted with AcOEt/hexane (1:4),then concentrated under reduced pressure to give 760 mg of a colorlesssyrup-like substance. The substance was recrystallized from AcOEt/hexane(1:3) to give 544 mg of a white columnar crystal (56%). 0003: --CH₂ CO₂Bh Yield 56%

Melting point: 162°-164° C. C₃₀ H₂₃ NO₄ (461, 492)

Elemental analysis Calcd.: 78.07, 5.02, 3.04 Found: 77.95, 5.20, 3.07

Mass (M/e) M⁺ 461, 167 (base peak)

IR (KBr): 1760, 1744, 1496, 1444, 1406, 1370, 1198, 1059, 748, 700

NMR (CDCl₃) δ 4.30 (2H, s), 6.87 (1H, s), 7.15˜7.50 (20H, m)

EXAMPLES 40 TO 43 ##STR59## According to the method similar to thatdescribed in Reference Example 1 except for reacting under the conditionindicated in the following table, the following compounds were produced.

                  TABLE 7                                                         ______________________________________                                        Example No.                                                                   (Compound                                                                     No.)    Reagent            Reaction condition                                 ______________________________________                                        40 (0044)                                                                              ##STR60##         at room temperature overnight                      41 (0086)                                                                              ##STR61##         at room temperature overnight                      42 (0099)                                                                              ##STR62##         at 0° C. for 6 hours                        43 (0109)                                                                              ##STR63##         at room temperature overnight                      ______________________________________                                    

EXAMPLE 40

Compound (0044) wherein R is n-butyl

Yield: 29%

Melting point: 62°-64° C.

IR (KBr): 1745, 1501, 1361, 1233, 1055, 770, 705

Mass (M/e)M⁺ 293

NMR (CDCl₃) δ 0.79 (3H, t), 1.10˜1.30 (2H, m), 1.38˜1.55 (2H, m), 3.47(2H, t)

EXAMPLE 41

Compound (0086) wherein R is a group represented by the formula:##STR64##

Yield: 53.9%

Melting point: 99°-101° C. C₂₀ H₁₄ NO₂ SCl (367, 843)

Elemental analysis Calcd.: 65.30, 3.84, 3.81, 8.72, 9.64 Found: 65.38,3.85, 3.85, 8.59, 9.58

IR (KBr) 1750, 1443, 1424, 1335, 1054, 998, 752, 702

Mass (M/e) M⁺ 367, 131 (base peak)

NMR (CDCl₃) δ 4.70 (2H,s), 6.46 (1H,d, 3.8 Hz), 6.66 (1H,d, 3.6 Hz),7.15˜7.30 (5H,m), 7.30˜7.45 (2H,m), 7.45˜7.60 (3H, m)

EXAMPLE 42

Compound (0099) wherein R is a group represented by the formula:##STR65##

Yield: 41.2%

Melting point: 85°-87° C. C₂₃ H₁₉ NO₃ (357, 39)

Elemental analysis: Calcd. 77.29, 5.36, 3.92 Found 77.33, 5.36, 3.98

IR (KBr) 1764, 1604, 1502, 1458, 1346, 1264, 1075, 756, 700

Mass(M/e) M⁺ 357 91 (base peak)

NMR (CDCl₃) δ 4.66 (2H, s), 4.99 (2H, s), 7.18˜7.40 (10H, m), 7.50 (5H,s)

EXAMPLE 43

Compound (0109) wherein R is a group represented by the formula:##STR66##

Yield: 77.2%

Melting point: 91°-93° C. C₂₁ H₁₈ N₂ O₃ (346, 37)

Elemental analysis Calcd.: 72.37, 5.29, 8.03 Found: (1/10 H₂ O), 72.44,5.27, 8.05

IR (KBr) cm⁻¹ 1752, 1601, 1498, 1445, 1384, 1340, 1250, 1204, 1051, 768,704

Mass(M/e) M+H!⁺ 347 (base peak)

NMR (CDCl₃) δ 1.84 (3H, s), 1.96 (3H, s), 4.51 (2H, s), 7.15, 7.30 (6H,m), 7.45˜7.56 (4H, m)

EXAMPLES 44 TO 49

According to the method similar to that described in Reference Example1, the reaction was conducted to give the compounds listed in thefollowing table.

                                      TABLE 8                                     __________________________________________________________________________     ##STR67##                                                                                             Melting                                              Example No.                                                                         Substituent R:     point(°C.)                                                                  IR(cm.sup.-1)KBr                                __________________________________________________________________________    44    CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                              81-83                                                                              1755, 1446, 1380,                               (0033)                        1023, 751, 700                                  45 (0042)                                                                            ##STR68##         161-163                                                                            1752, 1689, 1446, 1387, 1237, 759, 698          46 (0045)                                                                            ##STR69##         171-173                                                                            1746, 1601, 1502, 1380, 1057, 768, 702          47 (0049)                                                                            ##STR70##         110-112                                                                            1756, 1716, 1283, 1111, 751, 696                48 (0087)                                                                            ##STR71##         125-127                                                                            1744, 1370, 1051, 748, 701                      49 (0098)                                                                            ##STR72##         Foam- like                                                                         1755, 1602, 1518, 1342, 1054, 758,              __________________________________________________________________________                                  701                                         

EXAMPLE 50 ##STR73##

The compound 0033 (100 mg, 0.32 mmol) produced in Example 44 wasdissolved in EtOH (2 ml) and a solution of MeI (0.46 g, 3.2 mol) in EtOH(1 ml) was added at room temperature, and the mixture was allowed tostand overnight. A crystal precipitated was filtered and washed withcooled EtOH to give 43.5 mg of a colorless columnar crystal (compound0043, 30%).

Melting point: 237°-239° C. C₂₀ H₂₃ N₂ O₂ I (450.32)

Elemental analysis

Calcd.: 52.83, 5.22, 6.12, 28.15 Found: (1/5 H₂ O): 52.92, 5.20, 6.17,27.96

IR (KBr): 1745, 1448, 1378, 747

EXAMPLES 51 TO 59

    ______________________________________                                         ##STR74##                                                                    Example No                                                                    (Compound No.)                                                                          R                                                                   ______________________________________                                        51(0039)                                                                                 ##STR75##                                                          52(0047)                                                                                 ##STR76##                                                          53(0048)                                                                                 ##STR77##                                                          54(0062)                                                                                 ##STR78##                                                          55(0090)                                                                                 ##STR79##                                                          56(0091)                                                                                 ##STR80##                                                          57(0024)                                                                                 ##STR81##                                                          58(0056)                                                                                 ##STR82##                                                          59(0057)                                                                                 ##STR83##                                                          ______________________________________                                    

According to the method similar to that described in Reference Example 1except for using a 4,5-diphenyloxazol-2-one reagent explained in thefollowing Examples as a starting material, the above compounds weresynthesized. The yield and various data are described below.

EXAMPLE 51

3-(3-Fluorobenzyl)-4,5-diphenyl-oxazol-2-one (0039)

Starting material: m-Fluorobenzyl chloride

Yield 31%, oily substance

NMR δ (CDCl₃) ppm: 4.65 (s, 2H), 6.68 (d, J=9.4 Hz, 1H), 6.80 (d, J=7.8Hz, 1H), 6.92 (dd, J=8.2 and 8.2 Hz, 1H), 7.1˜7.3 (m, 8H), 7.4˜7.5 (m,3H)

EXAMPLE 52

3-(2-Fluorobenzyl)-4,5-diphenyl-oxazol-2-one (0047)

Starting material: o-Fluorobenzyl chloride

Yield 48%, oily substance

NMR (CDCl₃) ppm: 4.75 (s, 2H), 6.8˜7.3 (m, 11H), 7.3˜7.5 (m, 3H)

EXAMPLE 53

3-(4-Fluorobenzyl)-4,5-diphenyl-oxazol-2-one (0048)

Starting material: p-Fluorobenzyl chloride

Yield 65%

Melting point: 84° to 85° C., colorless crystal

NMR δ (CDCl₃) ppm: 4.63 (s, 2H), 6.8˜7.0 (m, 4H), 7.1˜7.3 (m, 7H),7.4˜7.6 (m, 3H)

EXAMPLE 54

Compound 0062

4,5-Diphenyloxazol-2-one (500 mg, 2.11 mmol) was dissolved in DMF (4 ml)and sodium hydride (153 mg, 2.55 mmol) was added under nitrogen and withice cooling over 20 minutes. After stirring for 20 minutes, propargylbromide (210 μl, 2.79 mmol) was added. After stirring for 15 minuteswith ice cooling and stirring at room temperature for 2 hours, water (20ml) was added and the mixture was extracted with ethyl acetate. Theextract was washed in turn with water and brine, dried over magnesiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography to give3-(2-propynyl)-4,5-diphenyl-oxazol-2-one.

Yield 45%

Melting point: 136°˜137° C. Colorless crystal

NMR δ (CDCl₃) ppm: 2.26 (t, J=2.6 Hz, 1H), 4.23 (m, J=2.6 Hz, 2H),7.2˜7.3 (m, 5H), 7.5˜7.6 (m, 5H)

EXAMPLE 55

3-(4-Phenoxybenzyl)-4,5-diphenyl-oxazol-2-one (0090)

Starting material: 4-Phenoxybutyl bromide

Yield 50%, oily substance

NMR δ (CDCl₃) ppm: 1.69 (m, 4H), 3.56 (m, 2H), 3.81 (m, 2H), 6.7˜7.0 (m,3H), 7.1˜7.3 (m, 7H), 7.3˜7.5 (m, 5H)

EXAMPLE 56

3-(2'-Pyridylmethyl)-4,5-diphenyl-oxazol-2-one (0091)

Starting material: 2-Picolyl chloride hydrochloride

Yield 3%, oily substance

NMR δ(CDCl₃) ppm: 4.79 (s, 2H), 7.2˜8.0 (m, 13H), 8.9 (d, J=4.6 Hz, 1H)

EXAMPLE 57

Compound 0024

4,5-Diphenyloxazol-2-one (100 mg, 0.42 mmol) was dissolved in pyridine(0.5 ml) and a solution of 4-(4'-phenyl)-butoxy-benzoyl chloride (134mg, 0.46 mmol) in pyridine (0.5 ml) was added with ice cooling. Afterone hour at room temperature, the mixture was treated in conventionalmanner to give 225 mg of the product. The product was subjected tosilica gel chromatography, and fractions eluted with hexane/EtOAc(85:15) are collected. Oily substance 95 mg

Yield: 46%

NMR δ (CDCl₃) ppm: 1.83 (m, 4H), 2.70 (t, J=4.8 Hz, 2H), 4.05 (t, J=4.8Hz, 2H), 6.93 (d, J=9.0 Hz, 2H), 7.14˜7.45 (m, 15H), 7.90 (d, J=9.0 Hz,2H)

EXAMPLE 58

Compound 0056, oily substance

NMR δ (CDCl₃) ppm: 3.72 (s, 3H), 4.64 (s, 2H), 6.5˜6.8 (m, 3H), 7.1˜7.6(m, 11H)

EXAMPLE 59

Compound 0057, melting point: 123°-124 ° C. (EtOAc)

NMR δ (CDCl₃): 4.26 (d, J=5.6 Hz, 2H), 6.07 (m, 1H), 6.23 (d, J=16.0 Hz,2H), 7.20˜7.6 (m, 15H).

EXAMPLES 60 TO 62 ##STR84## EXAMPLE 60

4,5-Bis-(4-methoxycarbonylphenyl)-3-oxazolin-2-one (0020)

(1) p-Methoxycarbonylbenzoin (0051)

N-Laurylthiazole bromide (2.01 g, 6 mmol) which was separatelysynthesized according to published literature W. Tagaki, Bull ChemicalSociety Japan (1980)! was dissolved in 1 liter of a phosphate buffer(0.5 mol, pH 8). Methyl 4-formyl benzoate (9.85 g, 60 mmol) was added tothe solution with stirring at room temperature and the mixture washeated at 55° C. for 6 hours. After standing at room temperature for 2days, the crystal precipitated was filtered and dissolved in ethylacetate. The solution was washed with water and dried over mirabilite,then filtered and concentrated. The resulting residue was recrystallizedfrom ethyl acetate to give 7.23 g of the product (73%).

Melting point: 143°˜147° C.

Elemental analysis (C₁₈ H₁₆ O₆) Calcd.: C, 65.85; H, 4.91 Found: C,65.56; H, 5.04

IR (Nujol) cm⁻¹ : 3454, 3424, 1722, 1678, 1609.

NMR (CDCl₃) δ: 3.88 (3H, s), 3.92 (3H, s), 4.54 (1H, brd, J=6.6 Hz),6.02 (1H, brd, J=4.2 Hz), 7.40 (2H, d, J=8.4 Hz), 7.90˜8.08 (6H, m).

(2) 4,5-Bis-(4-methoxycarbonylphenyl)-3-oxazolin-2-one (0020)

p-Methoxycarbonylbenzoin (2, 6.566 g, 20 mmol) obtained above was mixedwith ethyl carbamate (8.91 g, 100 mmol) and dried pyridine (1.62 ml, 20mmol) was added to the mixture. After heating at 160° C. for 2 hoursunder nitrogen gas, the mixture was cooled to precipitate a crystal, towhich was added ether (80 ml), and the crystal was filtered and washedto give 5.87 g of the titled compound (83%).

Melting point. 255°˜264° C.

Elemental analysis (C₁₉ H₁₅ NO₆.1/4 H₂ O) Calcd.: C, 63.77; H, 4.37; N,3.91 Found: C, 63.96; H, 4.38; N, 4.24

IR (KBr) cm⁻¹ : 1764, 1725, 1606

NMR (DMSO) δ: 3.84 (3H, s), 3.88 (3H, s), 6.42 (1H, brs), 7.50 (2H, d,J=8.8 Hz), 7.67 (2H, d, J=8.8 Hz), 7.92 (2H, d, J=8.8 Hz), 8.04 (2H, d,J=8.8 Hz).

EXAMPLE 61

3-Benzyl-4,5-bis-(4-methoxycarbonylphenyl)-3-oxazolin-2-one (0046)

4,5-bis-(4-methoxycarbonylphenyl)-3-oxazolin-2-one (3, 3.53 g, 10 mmol)obtained above was dissolved in dried DMF (50 ml), and benzyl bromide(3.57 ml, 30 mmol) and 60% NaH (600 mg, 15 mmol) were added withstirring at 0° C. under nitrogen gas. After stirring at room temperaturefor 4 hours, the reaction solution was poured into ice water andextracted with ethyl acetate. The extract was washed with water, dried,and concentrated. The resulting residue was subjected to silica gelchromatography to give 1.02 g of the titled compound (23%).

Elemental analysis (C₂₆ H₂₁ NO₆) Calcd.: C, 70.42; H, 4.77; N, 3.16Found: C, 70.20; H, 4.91; N, 3.16

Melting point. 54°˜58° C.

IR (CHCl₃) cm⁻¹ : 1753, 1718, 1608.

NMR (CDCl₃) δ: 3.07 (3H, s), 3.98 (3H, s), 4.69 (2H, s), 6.95˜7.00 (2H,m), 7.22˜7.32 (7H, m), 7.87 (2H, d, J=8.4 Hz), 8.10 (2H, d, J=8.4 Hz).

EXAMPLE 62

3-Benzyl-4,5-bis-(4-hydroxycarbonylphenyl)-3-oxazolin-2-one (0054)

3-Benzyl-4,5-bis-(4-methoxycarbonylphenyl)-3-oxazolin-2-one (4, 4.43 g,10 mmol) obtained in Example 61 was dissolved in methanol (50 ml), and1N-NaOH (50 ml, 50 mmol) was added with stirring and ice cooling. Afterstirring at room temperature for 4 hours, ice water (100 ml) and ethylacetate (100 ml) were added and the organic layer was washed with1N-NaOH and water. The combined aqueous layer was acidified (pH 3) withconcentrated hydrochloric acid with ice cooling and extracted with ethylacetate. The extract was washed with brine, and dried, and concentratedto give a residue (2.434 g) which was recrystallized from ether to give2.049 g of the titled compound (49%).

Melting point: 251°-256° C.

Elemental analysis (C₂₄ H₁₇ NO₆.1/2 H₂ O) Calcd.: C, 67.92; H, 4.28; N,3.30 Found: C, 68.08; H, 4.13; N, 3.10

IR (Nujol) cm⁻¹ : 3425 (br), 2660, 2542, 1733, 1688, 1606.

NMR (CDCl₃ +DMSO=7:1) δ: 4.70 (2H, s), 6.96˜7.01 (2H, m), 7.23˜7.36 (6H,m), 7.86 (2H, d, J=8.8 Hz), 8.08˜8.12 (2H+H, d).

EXAMPLES 63 TO 64 ##STR85##

According to the method similar to that described in Example 61 exceptfor using the compound 0020 produced in Example 60 as a startingmaterial, the reaction was conducted to give compounds 0023 and 0112.

EXAMPLE 63

Compound 0023

Melting point: 270°˜271° C.

Elemental analysis (C₂₄ H₂₃ NO₈) Calcd.: C, 63.57 H, 5.11 N, 3.09 Found:C, 63.62; H, 5.29 N, 3.00

IR (CHCl₃) cm⁻¹ : 1818, 1719, 1619.

NMR CDCl₃) δ: 1.25 (9H, s), 3.88 (3H, s) 3.98 (3H, s), 7.24 (2H, d,J=8.4 Hz), 7.49 (2H, d, J=8.4 Hz), 7.88 (2H, d, J=8.4 Hz) 8.17 (2H, d,J=8.4 Hz)

EXAMPLE 64

Compound 0112

Melting point: 143°˜144° C.

IR (CHCl₃) cm⁻¹ ; 1751, 1600

NMR (CDCl₃) δ; 4.66 (2H, s), 6.87˜7.26 (13H, m).

EXAMPLE 65

4,5-Bis-(4-hydrazinocarbonylphenyl)-3-oxazolin-2-one (0021) ##STR86##

4,5-Bis-(4-methoxycarbonylphenyl)-3-oxazolin-2-one (142 mg, 0.4 mmol)obtained in Example 60 was suspended in dried THF (1 ml) and hydrazineanhydride (256 μl, 40 mmol) was added, and the mixture was stirred atroom temperature under nitrogen. After the solid material was dissolvedin about 10 minutes, and stirring was continued for additional one hour,methylene chloride was added and the precipitate was filtered andrecrystallized from DMSO/water to give 71 mg of the titled compound (8)(50%).

Melting point: >300° C.

Elemental analysis (C₁₇ H₁₅ N₅ O₄.1/4 H₂ O) Calcd. C, 57.09; H, 4.37; N,19.57 Found: C, 57.50; H, 4.43; N, 18.81.

IR (KBr) cm⁻¹ : 3310, 1775, 1634, 1611.

NMR (DMSO) δ: 4.58 (4H, brs), 7.43 (2H, d, J=8.6 Hz), 7.58 (2H, d, J=8.6Hz), 7.79 (2H, d, J=8.6 Hz), 7.90 (2H, d, J=8.6 Hz), 9.85 (2H, d, J=20Hz), 11.51 (1H, brs).

EXAMPLES 66 TO 67 ##STR87##

The compound 0054 obtained in Example 62 was used to give the abovecompounds 0101 and 0102.

EXAMPLE 66

Compound 0101

Melting point: 260°˜267° C.

IR (Nujol) cm⁻¹ ; 3380, 3164, 1735, 1675, 1609

NMR (DMSO) δ; 4.70 (2H, S), 6.96˜7.01 (2H, m). 7.20˜7.24 (5H, m),7.35˜8.10 (10H, m)

EXAMPLE 67

Compound 0102

Melting point: 148°˜153° C.

IR (Nujol) cm⁻¹ ; 3322, 3282, 3180, 1741, 1668, 1606, 1550.

NMR (DMSO) δ: 4.53 (4H, brs), 4.66 (2H, s), 6.97˜7.02 (3H, m), 7.20˜7.26(4H, m), 7.49 (2H, d, J=8.2 Hz), 7.72 (2H, d, J=8.4 Hz), 7.92 (2H, d,J=8.2 Hz), 9.83 (2H, d, J=42.8 Hz).

EXAMPLES 68 TO 71 ##STR88## EXAMPLE 68

4,5-Bis-(4-hydroxycarbonylphenyl)-3-oxazolin-2-one (0022)

According to the method similar to that described in Example 62 exceptfor using the compound 0020 produced in Example 60 as a startingmaterial, the reaction was conducted to give compound 0022.

Melting point: >300° C.

IR (KBr) cm⁻¹ ; 3428, 1769, 1686, 1606.

NMR: (DMSO) δ; 7.52 (2H, d, J=8.6 Hz), 7.67 (2H, d, J=8.6 Hz), 7.94 (2H,d, J=8.6 Hz), 8.05 (2H, d, J=8.6 Hz), 11.64 (1H, brs).

EXAMPLE 69

4,5-Bis-(4-imidazocarbonyl phenyl)-3-oxazolin-2-one (0032)

4,5-Bis-(4-hydroxycarbonylphenyl)-3-oxazolin-2-one (compound 0022) (163mg, 0.5 mmol) produced in Example 68 was suspended in THF (10 ml) andCDI (1,1'-carbonyldiimidazole (170 mg, 1.05 mmol) was added withstirring. After heating the mixture with stirring at 60° C. for 5 hoursunder nitrogen gas, precipitated solid was filtered and washed withether, and then dried to give 170 mg of the dried titled compound (80%).

Melting point: >300° C.

Elemental analysis (C₂₃ H₁₅ N₅ O₄.3H₂ O) Calcd.: C, 57.62 ; H, 4.42 ; N,14.61 Found: C, 57.64 ; H, 4.12 ; N, 14.52.

IR (KBr) cm⁻¹ : 2842, 2750, 1742, 1604, 1541.

NMR (DMSO) δ: 5.78 (1H, brs), 7.04 (4H, s), 7.49 (2H, d, J=8.6 Hz), 7.63(2H, d, J=8.6 Hz), 7.68 (2H, s), 7.92 (2H, d, J=8.6 Hz), 8.02 (2H, d,J=8.6 Hz).

EXAMPLE 70

Compound 0052

The compound 0032 obtained in Example 69 was used to give compound 0052.

Melting point: >300° C.

Elemental analysis (C₁₇ H₁₃ N₃ O₄.1/4 H₂ O) Calcd.: C, 62.28 ; H, 4.15,N, 12.82 Found: C, 61.95; H, 4.02 ; N, 12.65

IR (Nujol) cm⁻¹ : 3434, 3188, 1758, 1655, 1609.

NMR (DMSO) δ: 7.44 (2H, d, J=8.2 Hz), 7.51 (2H, brs). 7.58 (2H, d, J=8.2Hz), 7.85 (2H, d, J=8.2 Hz), 7.95 (2H, d, J=8.2 Hz), 8.09 (2H, brs),11.55 (1H, brs) .

EXAMPLE 71

Compound 0100

(1) 4,5-Bis-(4-chlorocarbonylphenyl)-3-oxazolin-2-one (0053)

Oxazoline acid (12, 163 g, 0.5 mmol) obtained in Example 68 wassuspended in dried dichloromethane (2 ml), and DMF (13 μl, 1/10 amountof oxalyl chloride) was added with stirring, then oxalyl chloride (131μl, 1.5 mmol) was added thereto with stirring at 0° C. under nitrogengas. After standing at room temperature for 76 hours, dichloromethanewas added and precipitated solid was filtered and washed, and then driedto give 149 mg of the titled compound 0053 (82%).

Melting point: >300 ° C.

Elemental analysis (C₁₇ H₉ NO₄ Cl₂) Calcd.: C, 56.38; H, 2.50 N, 3.84;Cl, 19.58 Found: C, 55.94H, 2.76 N, 4.14; Cl, 16.03.

IR (Nujol) cm⁻¹ : 3170, 1766, 1725, 1686, 1597.

NMR (DMSO) δ: 7.49 (2H, d, J=8.2 Hz), 7.64 (2H, d, J=8.2 Hz), 7.92 (2H,d, J=8.2 Hz), 8.03 (2H, d, J=8.2 Hz), 11.69 (1H, s).

(2) 4,5-Bis-(4-(2-pyridino)methylaminocarbonylphenyl)-3-oxazolin-2-one(0100)

Acid chloride (0053, 72 mg, 0.2 mmol) obtained above was suspended indichloromethane (3 ml) and 2-(aminomethyl)pyridine (82 μl, 0.8 mmol) wasadded at room temperature with stirring, followed by additionalstirring. After 3 hours, the mixture was poured into ice water andextracted with dichloromethane/methanol (4:1). The resulting extract waswashed with water, dried, and concentrated to give a residue. Theresulting residue was separated with TLC (CHCL₃ :MeOH:H₂ O=32:6:0.5) andrecrystallized from ether to give 37 mg of the titled compound (0100)(36%).

Melting point; 115°˜118° C.

Elemental analysis (C₂₉ H₂₃ N₅ O₄.2H₂ O) Calcd.: C, 64.31; H, 5.03 N,12.93. Found: C, 64.28H, 4.99; N, 12.75.

NMR (CDCl₃) δ: 7.45 (4H, s), 7.15˜7.50 (8H, m), 7.65˜7.90 (6H, m),7.95-8.10 (2H, m), 8.41 (2H, dd, J=18.0, 4.0 Hz), 11.14 (1H, brs)

EXAMPLES 72 TO 74 ##STR89## EXAMPLE 72

5-(3-Bromopropylaminosulfonylphenyl)-4-phenyl-4-oxazolin-2-one (0031)

YI2 (300 mg, 89.3 μmol) produced in Example 1 (2) was dissolved in THF(30 ml) and triethylamine (300 μl, 89.3 μM×2.4) and 3-bromopropylaminehydrobromide (235 mg, 89.3 μM×1.2) were added in turn, and the mixturewas stirred at room temperature for 2 hours. The reaction solution wasconcentrated and partitioned between methyl ethyl ketone and watercontaining 2 ml of 2N hydrochloric acid. The organic layer was washed inturn with water and brine, and dried. After concentration, the crystalprecipitated was recrystallized from THF and methylene chloride to give230 mg of compound 0031 (59%).

Melting point: 232°-235° C.

¹ H NMR (DMSO): δ 1.88 (quintet, J=6.6 Hz, 2H), 2.87 (quartet, J=6.3 Hz,2H), 3.49 (t, J=6.4 Hz, 2H), 7.26-7.58 (m, 7H), 7.74 (d, J=8.6 Hz, 2H),11.56 (brs, 1H)

IR (Nujol): 3240, 3170, 1740, 1600, 1164 cm⁻¹

Elemental analysis (C₁₈ H₁₇ N₂ O₄ SBr.0.2H₂ O) Calcd. (%):C, 49.03; H,3.98; N, 6.35; S, 7.27 Found (%):C, 48.88; H, 3.95; N, 6.32; S, 7.19

EXAMPLE 73

5-(3-N-pyridiniumpropylaminosulfonylphenyl)-4-phenyl-4-oxazolin-2-onebromide (0028)

The compound 0031 (200 mg, 457 μmol) was dissolved in THF (15 ml), andpyridine (888 μl, 457 μmol×24) was added at room temperature, and themixture was stirred at 70° C. for 32 hours. The resulting precipitatewas filtered and washed with THF to give 238 mg of the objective crystalproduct 0028 (100%).

Melting point: 185°-188° C. (with decomposition)

¹ H-NMR (DMSO): δ 2.07 (quintet, J=7.0 Hz, 2H), 2.79 (quartet, J=6.0 Hz,2H), 4.63 (t, J=7.2 Hz, 2H), 7.48-7.59 (m, 7H), 7.73 (d, J=8.8 Hz, 2H),7.80 (t, J=5.6 Hz, 1H), 8.16 (t, J=7.1 Hz, 2H), 8.61 Hz(t, J=7.8 Hz,1H), 9.01 (d, J=4.0 Hz, 2H)

IR (Nujol): 3000, 1753, 1630, 1598, 1483, 1327, 1156 cm⁻¹

Element alanalysis (C₂₃ H₂₂ BrN₃ O₄ S.0.3H₂ O) Calcd. (%): C, 52.94; H,4.37; N, 8.05; S, 5.86; Br, 15.31 Found (%): C, 53.01; H, 4.60; N, 7.75;S, 5.86; Br, 15.06

EXAMPLE 74

5-(4-bromopropyloxysulfonyl)phenyl-4-phenyloxazolin-2-one (compound0041)

According to the method similar to that described in Example 72 exceptfor using n-BuLi in place of triethylamine and reacting 3-bromopropanolwith YI-2, the reaction was conducted to give the titled compound 0041.

Melting point: 167°-169° C.

IR (Nujol): 3190, 3020, 1760, 1750, 1728, 1602, 1185, 985, 922, 614cm⁻¹.

EXAMPLE 75

3-Benzyl-5-phenyl-4-oxazolin-2-one (compound 0073) ##STR90##

The compound described in published literature J. Org. Chem., 49, 2231(1984)!, 5-phenyl-4-oxazolin-2-one, was benzylated to give the titledcompound 0073.

Melting point: 158°-160° C.

¹ H NMR (CDCl₃): δ 4.80 (s, 2H), 6.63 (s, 1H), 7.21-7.49 (m, 10H)

IR (Nujol): 1743, 1496 cm⁻¹

Elemental analysis (%): C₁₆ H₁₃ NO₂.0.3H₂ O Calcd.:C, 74.87; H, 5.34; N,5.46 Found: C, 74.64; H, 5.10; N, 5.45

EXAMPLES 76 TO 77 ##STR91## EXAMPLE 76

Compound 0110

(1) Triphenylacetic acid (20.0 g, 69.4 mmol) was suspended in acetone(250 ml), and anhydrous potassium carbonate (57.5 g, 69.4 mmol×6) anddimethylsulfate acid (16.4 ml, 69.4 mmol×2.5) were added, and themixture was stirred at room temperature for 50 minutes. The reactionmixture was concentrated, and then partitioned between ethyl acetate and2N hydrochloric acid. The organic layer was washed in turn with waterand brine, dried. and concentrated. The crystal precipitated was washedwith ether to give 20.6 g of compound KS5 (yield 98%).

Melting point: 185°-186° C.

¹ H NMR (CDCl₃): δ 3.80 (s, 3H), 7.10-7.36 (m, 15H)

IR (Nujol): 1730, 1595, 1486, 1218, 1196, 1179, 1006 cm⁻¹

Elemental analysis (%) C₂₁ H₁₈ O₂ Calcd.:C, 83.42; H, 6.00 Found:C,83.43; H, 6.09

(2) Lithium aluminum hydride (2.56 g, 67.5 mmol) was suspended in THF(150 ml), to which was added a solution of the compound KS5 (20.4 g,67.5 mmol) in THF (300 ml) at room temperature over 45 minutes, and themixture was stirred for additional 30 minutes. Then, ethyl acetate andwater were added in turn with ice cooling to decompose the excessivereagent. The reaction solution was concentrated and the residue waspartitioned between ethyl acetate and 2N hydrochloric acid. The organiclayer was washed in turn with water and brine, and concentrated. Thecrystal precipitated was washed with ether/hexane to give 18.03 g of thecompound KS6 (yield 97%).

Melting point: 108°-109° C.

¹ H NMR (CDCl₃): δ 4.65 (s, 2H), 7.13-7.36 (m, 15H)

IR (Nujol): 3590, 1596, 1490, 1052, 1039 cm⁻¹

Elemental analysis (%) C₂₀ H₁₈ O Calcd.: C, 87.56; H, 6.61 Found: C,87.40; H, 6.67

(3) To a solution of dimethyl sulfoxide (11.11 ml, 65.2 mmol×2.4) inmethylene chloride (100 ml), oxalyl chloride (6.83 ml, 65.2 mmol×1.2)was added at -55° C., and the mixture was stirred at the sametemperature for 40 minutes. To the reaction mixture was dropwise added asolution of the compound KS6 (17.90 g, 65.2 mmol) in methylene chloride(200 ml) at -55° C. over 20 minutes. After stirring at the sametemperature for 40 minutes, triethylamine (27.28 ml, 65.2 mmol×3) wasdropwise added at the same temperature. After stirring at -55° C. for 10minutes, a cooling bath was removed and the temperature was graduallyincreased to room temperature. The organic layer was partitioned betweenethyl acetate and 2N hydrochloric acid. The reaction solution was washedin turn with water, aqueous 5% NaHCO₃ solution and brine, then dried.After concentration, the crystal precipitated was washed withether/hexane to give 16.91 g of the compound KS7 (yield 95%).

Melting point: 102°-104° C.

¹ H NMR (CDCl₃): δ 7.00-7.13 (m, 6H), 7.26-7.41 (m, 9H), 10.29 (s, 1H)

IR (Nujol): 1722, 1596, 1580, 1491, 1447, 1088, 754, 700, 587 cm⁻¹

Elemental analysis (%) C₂₀ H₁₆ O Calcd.: C, 88.20; H, 5.92 Found: C,88.02; H, 6.12

(4) To a solution of diisopropylamine (11.10 ml, 60.9 mmol×1.3) in THF(60 ml), a n-butyllithium/1.6N hexane solution (49.49 ml) was added at-25 ° C., and the mixture was stirred at the same temperature for 30minutes. The mixture was dropwise added to a solution of the compoundKS7 (16.59 g, 60.9 mmol) and methyl bromoacetate (6.92 ml, 60.9mmol×1.2) in THF (80 ml) at -25° C. After stirring at -25° C. for 15minutes, a cooling bath was removed and the temperature was graduallyincreased to room temperature. After the reaction solution wasconcentrated, the resulting residue was partitioned between ethylacetate and 2N hydrochloric acid. The organic layer was washed in turnwith water, aqueous 5% NaHCO₃ solution and brine, dried, and thenconcentrated. The resulting residue was purified by silica gel columnchromatography and recrystallized with methanol to give 9.69 g of thecompound KS8 (yield 46%).

Melting point: 110°-112° C.

¹ H NMR (CDCl₃): δ 3.04 (d, J=2.0 Hz, 1H), 3.79 (s, 3H), 4.25 (d, J=2.0Hz, 1H), 7.03-7.19 (m, 6H), 7.22-7.38 (m, 9H)

IR (Nujol): 1744, 1595, 1493, 1343, 1269, 1215, 1083, 1034, 1001, 949,903, 870, 838 cm⁻¹

Elemental analysis (%) C₂₃ H₂₀ O₃ Calcd.: C, 80.21; H, 5.85 Found: C,80.13; H, 5.99

(5) The compound KS8 (6.53 g, 19.0 mmol) was dissolved in dimethylsulfoxide (100 ml) and an aqueous 1N potassium hydroxide solution (37.9ml, 19.0 mmol×2) was added at 0° C., and the mixture was stirred at 0°C. for 5 minutes. The reaction solution was partitioned between ethylacetate and diluted hydrochloric acid containing ice. The organic layerwas washed in turn with water and brine. After the organic layer wasdried and concentrated, the resulting residue was recrystallized fromether/hexane to give 5.27 g of the compound KS9 (yield 84%).

Melting point: 142°-146° C. (decomposition point)

¹ H NMR (DMSO): δ 2.67 (d, J=2.0 Hz, 1H), 4.30 (d, J=2.0 Hz, 1H),6.98-7.14 (m, 6H), 7.26-7.42 (m, 9H)

IR (Nujol): 2560, 1724, 1596, 1492, 1270, 1228, 752, 743, 698 cm⁻¹

Elemental analysis (%) C₂₂ H₁₈ O₃ Calcd.: C, 79.98; H, 5.49 Found: C,79.61 ; H, 5.71

(6) The compound KS9 (7.11 g, 21.5 mmol) was suspended in methylenechloride (100 ml) and oxalyl chloride (6.57 ml, 21.5 mmol×3.5) and twodrops of dimethylformamide were added at 0° C., and the mixture wasstirred at room temperature for 40 minutes. The reaction solution wasconcentrated, and THF was added to the residue and was concentratedagain to give a pale yellow crystal. To the crystal, THF (100 ml) andtrimethylsilylazide (14.28 ml, 21.5 mmol×5.0) were added at roomtemperature, and the mixture was refluxed at 85° C. for 5 hours and 15minutes. The reaction solution was cooled, and then concentrated. Theresidue was partitioned between chloroform/methanol (9:1) and water. Theaqueous layer was extracted with chloroform/methanol (9:1) and theorganic layers were combined . This organic layer was washed with waterand dried, then concentrated to give a crystal which was washed withether to give 2.19 g of compound 0110 (yield 31%).

Melting point: >250° C.

¹ H NMR (DMSO): δ 6.32 (s, 1H), 6.98-7.08 (m, 6H), 7.27-7.41 (m, 9H),10.66 (s, 1H)

IR (Nujol): 3160, 3110, 1768, 1728, 1102, 962 cm⁻¹

Elemental analysis (%) C₂₂ H₁₇ NO₂.0.4H₂ O Calcd.: C, 78.98 ; H, 5.36 ;N, 4.19 Found: C, 79.09; H, 5.31; N, 4.46

EXAMPLE 77

Compound 0140

The compound KS10 (100 mg, 305 μmol) was dissolved in dimethylformamide(4 ml) and a solution of prenyl bromide (228 mg, 305 μmol×5.0) indimethylformamide (1 ml) was added at room temperature and sodiumhydride (13.4 mg, 305 μmol×1.1) was added at 0° C., and the mixture wasstirred at room temperature for 2 hours. The reaction solution waspartitioned between ethyl acetate and 2N hydrochloric acid. The organiclayer was washed in turn with water and brine, was dried and thenconcentrated. The crystal precipitated was washed with ether to give 76mg of compound 0140 (yield 63%).

Melting point: 163°-165° C.

¹ H NMR (CDCl₃): δ 1.68 (s, 3H), 1.73 (s, 3H), 4.12 (d, J=4.7 Hz, 2H),5.13-5.26 (m, 1H), 6.00 (s, 1H), 7.08-7.17 (m, 6H), 7.24-7.35 (m, 9H)

IR (Nujol): 1757, 1491, 757, 743, 701

Elemental analysis (%) C₂₇ H₂₅ NO₂.0.1H₂ O Calcd.: C, 81.62; H, 6.39; N,3.65 Found:C, 81.56; H, 6.38; N, 3.65

EXAMPLES 78 TO 80

According to the method similar to that described in Example 77, thereaction was conducted to give the compounds listed in the followingtable.

                                      TABLE 9                                     __________________________________________________________________________     ##STR92##                                                                                          Melting                                                 Example No.                                                                         Substituent: R  point (°C.)                                                                 IR (cm.sup.-1)                                     __________________________________________________________________________    78 (0114)                                                                            ##STR93##      150-151                                                                            (Nijol) 3150, 1752, 1475, 1394, 744, 700, 693      79 (0114)                                                                           PMZ             167-169                                                                            (Nijol) 1830, 1738, 1615, 1517, 1053, 1032         80 (0120)                                                                            ##STR94##      194-195                                                                            (Nijol) 3130, 1754, 1740, 1614, 1322, 1260,                                   1242, 1176, 1159, 1111, 1050                       __________________________________________________________________________

EXAMPLE 81

Compound 0029 ##STR95##

The compound described by Chung-gi et Shin at. al. Chem. Lett., 1171(1982)! was used as a starting material. To a solution of the methylester (1.50 g) in methanol (15 ml), 1N-NaOH (13.7 ml) was added and themixture was heated under reflux for 2 hours. The reaction solution waspoured into water, acidified with 2N-HCl, and then extracted with methylethyl ketone. The extract was washed with water and dried over magnesiumsulfate, then concentrated under reduced pressure to give a crystallineresidue. The residue was washed with ethyl ether to give 1.183 g of theobjective compound (0029) (91.0%).

Melting point: 215°˜216° C. (with decomposition)

Elemental analysis; C₁₀ H₇ NO₄ Calcd. C: 58.54 H: 3.44 N: 6.83 Found C:58.44 H: 3.56 N: 6.78

IR (νmax cm⁻¹, Nujol); 3185 br, 1748, 1760, 1639

NMR d-DMSO δ ppm; 3.37 (br, 1H), 7.40˜7.56 (m, 3H), 7.84˜7.98 (m, 2H),11.4 (s, 1H)

EXAMPLE 82

Compound 0030 ##STR96##

To a solution of the above carboxylic acid (205 mg, 1 mmol) intetrahydrofuran (10 ml) and dimethylformaide (5 ml),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD.HCl)(192 mg, 1 mmol) and N-hydroxybenzotriazole (135 mg, 1 mmol) were added,and the mixture was stirred for 30 minutes. Then,N-(2-aminoethyl)piperizine (157 μl, 1.1 mmol) was added and the mixturewas stirred at room temperature for 4 hours. The reaction solution waspoured into water, and extracted with methyl ethyl ketone. The extractwas washed with brine and dried over magnesium sulfate, and thenconcentrated under reduced pressure. The residue was subjected to SiO₂column chromatography and fractions eluted with methylenechloride/methyl alcohol (10:1) was collected to give a foam-like residue(228 mg). The residue was washed with ethyl ether to give 193 mg of theobjective compound as an amorphous form (61.0%).

Elemental analysis; C₁₇ H₂₁ N₃ O₃.0.7H₂ O Calcd. C: 62.25 H: 6.88 N:12.81 Found C: 62.51 H: 7.02 N: 12.53 5 μg/minutes hygroscopicity

IR νNujol max cm⁻¹ ; 3255, 1769, 1635, 1596, 1510

NMR δ d-MeOH ppm; 1.47˜1.79 (m, 6H), 2.72˜2.90 (m, 6H), 3.57 (t, J=6 Hz,2H), 7.34˜7.49 (m, 3H), 7.80˜7.90 (m, 2H)

EXAMPLE 83

Compound 0034 ##STR97##

The compound produced in Example 82 was converted into a quaternary saltwith CH₃ I by a conventional method.

Yield: 61%

Melting point: 200°˜201° C.

Elemental analysis; C₁₈ H₂₄ N₃ O₃ I0.2H₂ O Calcd. C: 46.90 H: 5.34 N:9.12 I: 27.54 Found C: 46.69 H: 5.25 N: 9.20 I: 27.53

IR (Nujol) νmax (cm⁻¹): 3280, 3135, 1778, 1667

NMR δ CD₃ OD (ppm): 1.60˜2.00 (m, 6H), 3.17 (s, 3H), 3.37˜3.83 (m, 8H),7.40˜7.50 (m, 3H), 7.74˜7.87 (m, 2H)

EXAMPLE 84

Compound 0079 ##STR98##

To a suspension of 60% sodium hydride (66 mg, 1.2×1.37 mmol) indimethylformamide (2 ml), a solution of a methyl ester (300 mg, 1.37mmol) in dimethylformamide (1.5 ml) was added under argon stream withice cooling. After stirring at the same temperature for 10 minutes,benzyl bromide (244 μl, 1.5×1.37 mmol) was added, and the mixture wasstirred at room temperature for one hour. The reaction solution waspoured into water, and extracted with ethyl acetate. The extract waswashed in turn with 2N-HCl, 5% NaHCO₃ and H₂ O, then dried overmagnesium sulfate and concentrated under reduced pressure. The residuewas subjected to SiO₂ column chromatography and fractions eluted withn-hexane/ethyl acetate (4:1) were collected, followed byrecrystallization from n-hexane to give 270 mg of the objective compound(63.7%).

Melting point: 51°˜52° C.

Elemental analysis; C₁₈ H₁₅ NO₄ Calcd. C: 69.89 H: 4.89 N: 4.53 Found C:69.96 H: 4.82 N: 4.64

IR νCHCl₃ max cm⁻¹ ; 1765, 1722, 1498

NMR δ CDCl₃ ppm; 3.74 (s, 3H), 5.18 (s, 2H), 7.28˜7.48 (m, 8H),7.68˜7.78 (m, 2H)

EXAMPLE 85

Compound 0080 ##STR99##

Yield: 75%

Melting point: 160°˜163° C.

Elemental analysis; C₃₀ H₂₃ N₁ O₄ Calcd. C: 78.07 H: 5.02 N: 3.04 FoundC: 78.31 H: 4.94 N: 3.05

IR (CHCl₃) νmax (cm⁻¹): 1770, 1732, 1600, 1498

NMR δ CDCl₃ (ppm): 3.21 (s, 3H), 7.20˜7.63 (m, 20H)

EXAMPLE 86

Compound 0081 ##STR100##

The compound 0079 produced in Example 84 was hydrolyzed with1N-NaOH/MeOH by a conventional method to give compound 0081.

Yield: 82%

Melting point: 179°˜182° C.

Elemental analysis; C₁₇ H₁₃ NO₄ Calcd. C: 69.14 H: 4.44 N: 4.74 Found C:68.89 H: 4.42 N: 4.71

IR (Nujol) νmax (cm⁻¹): 2220˜3290 (br), 1729, 1697, 1617, 1498

NMR (d₆ -DMSO) δ ppm: 2.80˜4.10 (br, 1H), 5.11 (s, 2H), 7.20˜7.55 (m,8H), 7.70˜7.80 (m, 2H)

EXAMPLE 87

Compound 0082 ##STR101##

Melting point: 208˜210 (decomposition)

NMR (d₆ -DMSO) δ (ppm): 3.38 (br, 1H), 7.40˜7.52 (m, 12H), 7.84˜7.95 (m,8H)

IR (Nujol) νmax (cm⁻¹): 2500˜3350 br, 1745, 1694, 1640, 1480, 1375

EXAMPLES 88 TO 89 ##STR102##

The amine (1 eq) was added to a solution of4,5-diphenyl-1,3-dioxol-2-one in DMF (4 ml), and the mixture was stirredat room temperature. After the completion of the reaction, ethyl acetate(8 ml) and 0.5N hydrochloric acid (10 ml) were added, and the mixturewas stirred and extracted. The organic layer was washed with water, andthen dried over Na₂ SO₄. After the solvent was distilled off underreduced pressure, CF₃ CO₂ H was added to the residue at roomtemperature, and the solution was stirred overnight. After CF₃ CO₂ H wasdistilled off under reduced pressure, CH₂ Cl₂ was added and the mixturewas washed with alkali and water, then dried over Na₂ SO₄. After theorganic solvent was distilled off, the residue was recrystallized fromEtOH.

Physico-chemical properties of the resulting compounds are shown inExamples 88 and 89.

EXAMPLE 88

Compound 0092 ##STR103## White crystal

Melting point: 99°˜101° C.

¹ H-NMR (CDCl₃) δ: 1.74-1.90 (2H, m), 2.52 (2H, t, J=7.5 Hz), 3.52 (2H,t, J=7.5 Hz), 6.97-7.52 (15H, m)

(M,S)m/z 355 (M⁺)

Elemental analysis Calcd.: C: 81.1 H: 5.96 N: 3.94 Found: C: 80.94 H:5.95 N: 3.93

IR (cm⁻¹, KBr): 695, 745, 760, 1365, 1445, 1495, 1600, 1755, 2950, 3020,3400

EXAMPLE 89

Compound 0108 ##STR104## Colorless oily product

¹ H-NMR (CDCl₃) δ: 1,41-1.56 (4H, m), 2.51 (2H, t, J=7.5 Hz), 3.50 (2H,t, J=7.5 Hz), 7.05-7.53 (15H, m)

M,S m/z: 370 M+H!⁺ 739 2M+H!⁺

IR (cm⁻¹, neat): 700, 755, 765, 1025, 1055, 1360, 1390, 1450, 1500,1605, 1760, 2950

Reference Example 2 ##STR105## Process 1: (1)→(2)

To a solution of L-(+)-phenylglycine methyl ester hydrochloride (1 g)and CbzCl (1.1 eq, 0.928 g) in CH₃ CN/Water (2:1), an aqueous solution(50 ml) of K₂ CO₃ (5 eq) was dropwise added at 0° C. After completion ofthe reaction, the reaction solution was extracted with ethyl acetate andpurified with silica gel to give 1.42 g of a white solid (yield 96%).

Data (S isomer) of compound (2)

¹ H-NMR (CDCl₃) δ: 3.72 (s, 3H), 5.09 (s, 2H), 5.38 (d, 1H, J=7.5 Hz),5.82˜5.86 (br, 1H) 7.34 (s, 10H)

α!_(D) =-114.6°±1.5° (CHCl₃, C=1.002, 24° C.)

Melting point: 66° C.

Process 2: (2)→(4)

Et₂ O (100 ml) in which the compound (2) (1.89 g) was dissolved wascooled to -78° C. under N₂ atmosphere and DIBAL (THF solution) (1.2 eq)was dropwise added at the same temperature. After one hour, a solutionof phenyl magnesium bromide (4 eq) in THF was dropwise added, and themixture was heated to room temperature. After stirring overnight, thereaction was terminated with aqueous NH₄ Cl. Then, the reaction solutionwas extracted with ethyl acetate and purified by silica gel to give 1.46g of a white solid (compound (3), yield 67%).

The compound (3) was dissolved in a mixed solvent 7.5NKOH:THF:MeOH=4:2:1), and the mixture was stirred at room temperatureovernight. After neutralizing with 1N hydrochloric acid, the mixture wasextracted with ethyl acetate and purified by silica gel chromatography.

Data (S isomer) of compound (4) (4s, 5s)

¹ H-NMR (CDCl₃) δ: 4.76 (d, 1H, J=7.4 Hz), 5.30 (d, 1H, J=74 Hz), 5.90(s, 1H), 7.26-7.41 (m, 10H)

α!_(D) =-63.7°±1.0° (C=1.008, CHCl₃, 24° C.)

Melting point: 131° C.

Reference Example 3 ##STR106##

According to the method similar to that described in Reference Example 2except for using D-(-)-phenylglycine methyl ester hydrochloride as astarting material, the reaction was conducted.

¹ H-NMR (CDCl₃) δ: 4.77 (d, 1H, J=7.4 Hz), 5.26 (d, 1H, J=7.4 Hz), 6.45(s, 1H), 7.27˜7.42 (m, 10H)

α!_(D) =+62.4°±1.0° (C=1.013, CHCl₃, 25° C.)

Melting point: 133° C.

M.S: m/z 239 (M⁺), 107 (base peak)

EXAMPLE 90 ##STR107##

(1R, 2S)-(-)-2-Amino-1,2-diphenylethanol (8.58 g) and Et₃ N (1 ml) weredissolved in THF (150 ml). After the solution was cooled to 0° C.,triphosgene 3.86 g) was added and the mixture was heated to roomtemperature after stirring for 5 minutes. After completion of thereaction, the reaction was terminated with water. After stirring for 30minutes, the reaction solution was extracted with ethyl acetate. Afterthe organic solvent was distilled off, the residue was recrystallizedfrom ethyl acetate to give 6.44 g of compound 0161 as a white solid(yield 67%).

¹ H-NMR (CDCl₃) δ: 5.19 (d, 1H, J=8.2 Hz), 5.96 (d, 1H, J=8.2 Hz), 5.76(s, 1H), 6.92-7.14 (m, 10H)

α!_(D) =-75.4°±1.1° (C=1.016, CHCl₃, 23° C.)

Melting point: 232° C.

EXAMPLE 91 ##STR108##

According to the method similar to that described in Example 90 exceptfor using (1S, 2R)-(+)-2-amino-1,2-diphenylethanol as a startingmaterial, the reaction was conducted.

¹ H-NMR (CDCl₃) δ: 5.19 (d, 1H, J=8.2 Hz), 5.96 (d, 1H, J=8.2 Hz), 5.46(s, 1H), 6.92-7.15 (m, 10H)

α!_(D) =+75.3°±1.2° (C=1.001, CHCl₃, 23.5° C.)

Melting point: 229° C.

M.S: m/z 240 M+H!⁺, 479 2M+H!⁺

IR: cm⁻¹ KBr 3400, 3270, 1745, 1710, 1496, 1452, 1351, 1235, 1092, 979,762, 715, 696

Reference Example 4 ##STR109##

According to the method similar to the production process of (4S,5S)-4,5-diphenyl-oxazolin-2-one in Reference Example 2 except for usingthiophenyl magnesium bromide in place of phenyl magnesium bromide, thereaction was conducted.

¹ H-NMR (CDCl₃) δ: 4.95 (d, 1H, J=7.5 Hz), 5.50 (d, 1H, J=7.5 Hz), 5.59(br, 1H) 6.75-7.10 (m, 2H), 7.28-7.48 (m, 6H)

α!_(D) =-133.2°±1.7° (C=1.000, CHCl₃, 24° C.)

Melting point: 138° C.

Reference Example 5 ##STR110##

To a DMF solution of oxazoline was added alkyl halide (more than 1.5eq), then NaH (2 eq) at 0° C. under N₂ atmosphere. After completion ofthe reaction, the reaction solution was extracted with ethyl acetate andpurified by silica gel chromatography.

Example 92 ##STR111##

To a solution of (4R, 5R)-4,5-diphenyl-oxazolin-2-one (84.5 mg, 0.353mmol) in DMF was added 2-fluoro-benzyl chloride (1,7 eq), then NaH (3eq) at 0° C. under N₂ atmosphere, and the mixture was stirred whilemaintaining the temperature at 0° C. After completion of the reaction,the reaction solution was extracted with ethyl acetate and purified bysilica gel chromatography to give a colorless oily product (107.1 mg,yield 87%).

Colorless oily product

¹ H-NMR (CDCl₃) δ: 3.74 (1H, d, J=15 Hz), 4.31 (1H, d, J=7.5 Hz), 4.89(1H, d, J=15 Hz), 5.30 (1H, d, J=7.5 Hz), 6.78-7.48 (14H, m)

M,S: 347 (M⁺) 132 (base peak)

EXAMPLES 93 TO 109

According to the method similar to that described above, the followingcompounds were synthesized.

EXAMPLE 93

Compound 0168 ##STR112## White crystal

Melting point: 109°˜110° C.

¹ H-NMR (CDCl₃) δ: 3.71 (1H, d, J=15 Hz), 4.82 (1H, d, J=7.5 Hz), 5.01(1H, d, J=15 Hz), 5.81 (1H, d, J-7.5 Hz), 6.79-7.34 (14H, m)

M,S m/z 347 (M⁺) 132 (base peak)

α!_(D) +79.8°±1.2° (C=1.00, CHCl₃, 23° C.)

EXAMPLE 94

Compound 0169 ##STR113## White crystal

Melting point: 78°˜79° C.

¹ H-NMR (CDCl₃) δ: 1.28 (3H, s), 1.63 (3H, s), 1.73 (3H, s), 1.94-2.12(4H, m), 3.40 (1H, dd, J=10 Hz, 15 Hz), 4.25 (1H, dd, J=6.3 Hz, 15 Hz),4.99 (1H, d, J=8.8 Hz), 5.04-5.24 (2H, m), 5.81 (1H, d, J=8.8 Hz),6.78-7.20 (10H, m)

α!_(D) +25.3°±0.7° (C=1.00, CHCl₃, 23° C.)

EXAMPLE 95

Compound 0181 ##STR114## White crystal

Melting point: 106°˜107° C.

¹ H-NMR (CDCl₃) δ: 3.71 (1H, d, J=15 Hz), 4.83 (1H, d, J=8.8 Hz), 5.00(1H, d, J=15 Hz), 5.80 (1H, d, J=8.8 Hz), 6.78-7.35 (14H, m)

M,S m/z 348 M+H!⁺ 695 2M+H!⁺

Elemental analysis Calcd.: C: 76.07 H: 5.22 F: 5.47 N: 4.03 Found: C:76.00 H: 5.32 F: 5.55 N: 4.03

α!_(D) -82.4°±1.2° (C=1.00, CHCl₃, 24° C.)

IR (cm⁻¹, KBr) 698, 705, 764, 1018, 1227, 1417, 1455, 1745, 3430 (br)

EXAMPLE 96

Compound 0182 ##STR115## White crystal

Melting point: 80°˜81° C.

¹ H-NHR (CDCl₃) δ: 1.27 (3H, s), 1.62 (3H, s), 1.72 (3H, s), 1.94-2.12(4H, m), 3.40 (1H, dd, J=10 Hz, 15 Hz), 4.25 (1H, dd, J=6.3 Hz, 15 Hz),5.00 (1H, d, J=8.8 Hz), 5.04-5.24 (2H, m), 5.81 (1H, d, J=8.8 Hz),6.78-7.20 (10H, m)

M,S 376 M+H!⁺, 751 2M+H!⁺

Elemental analysis Calcd.: C: 79.96 H: 7.78 N: 3.73 Found: C: 79.46 H:7.87 N: 3.79

α!_(D) -26.9°±0.7° (C=1.01, CHCl₃, 24° C.)

IR (cm⁻¹, KBr) 698, 760, 1021, 1235, 1425, 1455, 1730, 2910, 3420 (br)

EXAMPLE 97

Compound 0199 ##STR116## White crystal

Melting point: 96°˜97° C.

¹ H-NMR (CDCl₃) δ: 3.86 (1H, d, J=15 Hz), 4.96 (1H, d, J=8.8 Hz), 5.01(1H, d, J=15 Hz), 5.79 (1H, d, J=8.8 Hz), 6.57 (1H, d, J=3.8 Hz),6.76-7.26 (11H, m)

M,S 369 (M⁺) 180 (base peak)

α!_(D) 132.3°±1.7° (C=1.01, CHCl₃, 25° C.)

IR (cm⁻¹, KBr) 695, 760, 802, 995, 1020, 1231, 1369, 1410, 1462, 1497,1735, 3030, 3440 (br)

EXAMPLE 98

Compound 0213 ##STR117## Colorless oily product

¹ H-NMR (CDCl₃) δ: 1.26 (3H, s), 1.56 (3H, s), 1.58 (3H, s), 1.84-2.06(4H, m), 3.40 (1H, dd, J=10 Hz, 13.8 Hz), 4.17 (1H, dd, J=6.3 Hz, 13.8Hz), 4.48 (1H, d, J=7.5 Hz), 4.95-5.13 (2H, m), 5.22 (1H, d, J=7.5 Hz),7.18-7.47 (10H, m)

M,S 375 (M⁺) 180 (base peak)

EXAMPLE 99

Compound 0246 ##STR118## Colorless oily product

¹ H-NMR (CDCl₃) δ: 3.86 (1H, d, J=15 Hz), 4.43 (1H, d, J=7.5 Hz), 4.92(1H, d, J=15 Hz), 5.27 (1H, d, J=7.5 Hz), 6.54 (1H, d, J=3.8 Hz), 6.72(1H, d, J=3.8 Hz), 7.12-7.51 (10H, m)

M,S m/z 369 (MH⁺) 180 (base peak)

EXAMPLE 100

Compound 0247 ##STR119## White crystal

Melting point: 87°˜88° C.

¹ H-NMR (CDCl₃) δ: 1.33-1.65 (4H, m), 2.40-2.70 (2H, m), 2.83 (1H, dt,Jd=13.8 Hz, Jt=6.3), 3.54 (1H, dt Jd=13.8 Hz Jt=7.5 Hz), 4.43 (1H, d,J=7.5 Hz), 5.22 (1H, d,=7.5 Hz), 7.00-7.50 (15H, m)

M,S m/z 371 (M⁺) 91 (base peak)

EXAMPLE 101

Compound 0288 ##STR120## Colorless oily product

¹ H-NMR (CDCl₃) δ: 1.26 (3H, s), 1.55 (3H, s), 1.58 (3H, s), 1.84-2.06(4H, m), 3.40 (1H, dd, J=10 Hz, 13.8 Hz), 4.17 (1H, d, d, J=6.3 Hz, 13.8Hz), 4.48 (1H, d, J=17.5 Hz), 4.95-5.13 (2H, m), 5.22 (1H, d, J=7.5 Hz),7.18-7.47 (10H, m)

M,S m/z 375 (M⁺) 180 (base peak)

α!_(D) -71.3°±1.2° (C=0.96, CHCl₃, 23° C.)

Elemental analysis Calcd.: C: 79.96 H: 7.78 N: 3.73 Found C: 79.68 H:7.92 N: 3.87

IR (cm⁻¹, neat) 700, 760, 1034, 1198, 1278, 1404, 1457, 1760, 2917, 2966

EXAMPLE 102

Compound 0289 ##STR121## Colorless oily product

¹ H-NMR (CDCl₃) δ: 1.33-1.64 (4H, m), 2.40-2.70 (2H, m), 2.83 (1H, dt,Jd=13.8 Hz, Jt=6.3 Hz), 3.54 (1H, dt, Jd=13.8 Hz Jt=7.5 Hz), 4.43 (1H,d, J=7.5 Hz), 5.22 (1H, d, J=7.5 Hz), 7.00-7.48 (15H, m)

M,S m/z 371 (M⁺) 91 (base peak)

EXAMPLE 103

Compound 0296 ##STR122## Colorless oily product

¹ H-NMR (CDCl₃) δ: 1.47 (3H, s), 1.56˜1.92 (10H, m), 3.40 (1H, dd, J=8.8Hz, 15 Hz), 4.06-4.18 (1H, m), 4.51 (1H, d, J=7.5 Hz), 4.82-4.94 (1H,m), 5.04-5.14 (1H, m), 5.21 (1H, d, J=7.5 Hz), 7.20-7.50 (10H, m)

M,S m/z 375 (M⁺) 180 (base peak)

α!_(D) +91.7°±1.3° (C=1.03, CHCl₃, 26° C.)

Elemental analysis Calcd.: C: 79.96 H: 7.78 N: 3.73 Found: C: 79.61 H:7.87 N: 3.85

EXAMPLE 104

Compound 0313 ##STR123## Colorless oily product

¹ H-NMR (CDCl₃) δ: 1.47 (3H, s), 1.56-1.92 (10H, m), 3.39 (1H, dd, J=8.8Hz, J=15 Hz), 4.06-4.18 (1H, m), 4.51 (1H, d, J=7.5 Hz), 4.82-4.94 (1H,m), 5.04-5.14 (1H, m), 5.21 (1H, d, J=7.5 Hz), 7.20-7.50 (10H, m)

M,S m/z 375 (M⁺) 180 (base peak)

EXAMPLE 105

Compound 0315 ##STR124## Colorless oily product

¹ H-NMR (CDCl₃) δ: 1.61 (3H, s), 1.66 (3H, s), 1.71 (3H, s), 2.00-2.20(4H, m), 2.63 (1H, dd, J=7.5 Hz, 13.8 Hz), 3.12 (1H, dd, J=3.8 Hz, 11.3Hz), 3.75 (1H, dd, J=7.5 Hz, 13.8 Hz), 3.88-4.24 (4H, m), 5.00-5.24 (2H,m), 7.07-7.40 (5H, m)

M,S m/z 313 (M⁺) 69 (base peak)

Elemental analysis Calcd.: C: 76.64 H: 8.68 N: 4.47 Found: C: 75.78 H:8.67 N: 4.39

α!_(D) -92.4°±1.2° (C=1.28, CHCl₃, 25° C.)

EXAMPLE 106

Compound 0325 ##STR125## Colorless oily product

¹ H-NMR (CDCl₃) δ: 1.29 (3H, s), 1.56 (3H, s), 1.64 (3H, s), 1.90-2.05(4H, m), 3.42 (1H, dd, J=15 Hz, 8.8 Hz), 4.12-4.23 (1H, m), 4.66 (1H, d,J=7.6 Hz), 5.41 (1H, d, J=7.6 Hz), 6.95-7.02 (2H, m), 7.21-7.46 (6H, m)

M,S 381 (M⁺) 186 (base peak)

Elemental analysis Calcd.: C: 72.41 H: 7.13 N: 3.67 S: 8.4 Found: C:72.37 H: 7.25 N: 3.72 S: 8.31

α!_(D) -123.5°±2.0° (C=0.80, CHCl₃, 23° C.)

IR (cm⁻¹, neat) 702, 1378, 1404, 1438, 1454, 1668, 1761, 1916, 2966

EXAMPLE 107

Compound 0346 ##STR126## Colorless oily product

¹ H-NMR (CDCl₃) δ: 0.83 (3H, d, J=6.3 Hz), 0.90-1.53 (8H, m), 1.65 (3H,s), 1.78-1.95 (2H, m), 2.70-2.90 (1H, m), 3.45-3.65 (1H, m), 4.53 (1H,d, J=6.3 Hz), 4.94-5.07 (1H, m), 5.23 (1H, d, J=6.3 Hz), 7.20-7.48 (10H,m)

M,S m/z 377 (M+) 180 (base peak)

Elemental analysis Calcd.: C: 79.54 H: 8.28 N: 3.71 Found: C: 79.18 H:8.34 N: 3.74

α!_(D) -28.6±0.7 (C=1.06, CHCl₃, 23° C.)

IR (cm⁻¹, neat) 700, 758, 1022, 1036, 1411, 1457, 1760, 2915, 2962

EXAMPLE 108

Compound 0347 ##STR127## Colorless oily product

¹ H-NMR (CDCl₃) δ: 0.81 (3H, d, J=6.3 Hz), 0.90˜1.53 (8H, m), 1.65 (3H,s) 1.78-1.95 (2H, m), 2.70-2.90 (1H, m), 3.45-3.65 (1H, m), 4.52 (1H, d,J=6.3 Hz), 4.94-5.07 (1H, m), 5.23 (1H, d, J=6.3 Hz), 7.20-7.48 (10H, m)

M,S m/z 377 (M⁺) 180 (base peak)

Elemental analysis Calcd.: C: 79.54 H: 8.28 N: 3.71 Found: C: 79.15 H:8.34 N: 3.76

α!_(D) -14.4°±0.5° (C=1.07, CHCl₃, 23° C.)

IR (cm⁻¹, neat) 700, 758, 1022, 1376, 1412, 1457, 1759, 2915, 2962

EXAMPLE 109

Compound 0303 ##STR128##

¹ H-NMR (CDCl₃) δ: 1.27 (s, 3H), 1.56 (s, 3H), 1.59 (s, 3H), 1.68 (s,3H), 1.80˜2.10 (m, 8H), 3.41 (dd, 1H, J=15 Hz, J=10 Hz), 4.16 (dd, 1H,J=15 Hz, J=7.5 Hz), 4.49 (d, 1H, J=8.8 Hz), 4.96-5.16 (m, 3H), 5.21 (d,1H, J=8.8 Hz), 7.20-7.50 (m, 10H)

M.S m/z 180 (base peak), 443 M⁺ !, 444 MH^(+!)

EXAMPLES 110 TO 115

According to the method similar to that described above, the followingcompounds were produced.

                                      TABLE 10                                    __________________________________________________________________________     ##STR129##                                                                                          Melting                                                Example No.                                                                          Substituent: R  point (°C.)                                                                  IR (cm.sup.-1)                                   __________________________________________________________________________    110 (0198)                                                                            ##STR130##     118   (Nijol) 3420, 3030, 2920, 1725, 1496, 1452,                                   1425, 1275, 1021, 757, 595                       111 (0236)                                                                            ##STR131##     144-145                                                                             (KBr) 3456, 2959, 2851, 1740, 1455, 1419,                                     12636, 1118, 702                                 112 (0237)                                                                            ##STR132##     135-136                                                                             3452, 3027, 2912, 1761, 1453, 1389, 1039,                                     1026, 702                                        113 (0244)                                                                            ##STR133##     Amor- phous                                                                         3449, 3031, 1756, 1455, 1225, 1164, 1025,                                     760, 697                                         __________________________________________________________________________

EXAMPLE 114

Compound 0245 ##STR134## White crystal

Melting point: 83°˜84° C.

IR: (KBr) 701, 988, 1154, 1407, 1733, 1744, 2988, 3085, 3451 cm⁻¹

M.S m/z 359 M+! 91 (base peak)

α!_(D) 16.2°±0.6° (C=1.018, CHCl₃, 25° C.)

EXAMPLE 115

Compound 0326 ##STR135## White amorphous powder

IR: (KBr) 700, 763, 987, 1235, 1410, 1456, 1487, 1563, 1594, 1757, 2821,2942 cm⁻¹.

MS m/z 475 M⁺ ! 209 (base peak)

EXAMPLES 116 TO 120 ##STR136## EXAMPLE 116

5-(4-Biphenyl)-4-phenyloxazolin-2-one (I-34) (0088)

(1) Methyl 3-(4-biphenyl)-2,3-epoxy-2-phenyl propionate (I-31)

To a solution of biphenylaldehyde (5.60 g, 30.72 mmol) in MeOH (169 ml),Na (742 mg, 32.26 mmol) and bromo-methyl ester (I-30) (7.04 g, 30.72mmol) were added, and the mixture was stirred at room temperature for1.5 hours. Water (200 ml) was added to the reaction solution and thecrystal precipitated was filtered. The crystal was dissolved in CH₂ Cl₂and the solution was dried over MgSO₄, and the solvent was distilled offunder reduced pressure to give 8.20 g of a crystalline residue. Theresidue was purified by silica gel chromatography (SiO₂ 430 g; elutedwith toluene/n-hexane (1:1) and toluene) to give a crystal (3.80 g),which was recrystallized from CH₂ Cl₂ /diethyl ether/n-hexane to give3.41 g of a colorless needle crystal (33.5%).

Melting point: 148.0°˜149.0° C.

Elemental analysis (C₂₂ H₁₈ O₃ (MW=330.383)): Calcd.: C, 79.98; H, 5.49Found: C, 80.09; H, 5.44

IR (CHCl₃): 1738, 1601, 1566, 1488, 1449, 1436, 1412, 1386 cm⁻¹

NMR (CDCl₃): δ 3.815 (s, 3H), 4.604 (s, 1H), 7.01˜7.13 (m, 2H),7.18˜7.43 (m, 10H), 7.43˜7.54 (m, 2H)

(2) Sodium 3-(4-biphenyl)-2,3-epoxy-2-phenyl propionate (I-32)

To a solution of an aqueous 1N-NaOH solution (11.9 ml, 11.96 mmol) inmethanol (53 ml)/THF (35 ml), methyl ester (I-31) (3.76 g, 11.39 mmol)was dissolved, and the mixture was stirred with ice cooling for 40minutes, then stirred at room temperature for 3 hours. The solvent ofthe reaction mixture was distilled off under reduced pressure and theresidue was washed with Et₂ O to give 3.183 g of a colorless needlecrystal (82.6%).

Elemental analysis (C₂₁ H₁₅ O₃ Na (MW=338.338)): Calcd.: C, 74.55; H,4.47; Na, 6.79 Found: C, 74.50; H, 4.58; Na, 6.81

IR (nujol): 3620, 3405, 3062, 3035, 1610, 1489, 1449, 1392 cm⁻¹

NMR (CD₃ OD): δ 4.415 (s, 1H), 7.03˜7.43 (m, 12H), 7.43˜7.54 (m, 2H)

The solvent of the washing solution was distilled off under reducedpressure and the residue was acidified by adding aqueous HCl, then themixture was extracted with ethyl acetate. The ethyl acetate layer wasdried, and then the solvent was distilled off to give 686 mg of freecarboxylic acid as a colorless crystal (19%).

(3) 5-(4-Biphenyl)-4-phenyloxazolin-2-one (I-34) (0088)

To a solution of a Na salt (I-32) (2.74 g, 8.11 mmol) in THF (40 ml),oxalyl chloride (14.5 ml, 162 mmol) was dropwise added with ice cooling,and the mixture was stirred at the same temperature for one hour and 20minutes. After stirring at room temperature for additional 1.5 hours,the solvent was distilled off under reduced pressure. The resultingresidue was dissolved in THF (40 ml), and then Me₃ SiN₃ (5.66 ml, 40.55mmol) was added, and the mixture was heated under reflux for 3 hours and15 minutes. The solvent of the reaction solution was distilled off andthe residue was dissolved in CHCl₃ /MeOH (9:1), and then the solutionwas washed with water and dried, then the solvent was distilled off. Theresulting crystalline residue of cream color was purified by silica gelchromatography (SiO₂ : 18.7 g, eluent: CH₂ Cl₂ & CH₂ Cl₂ /MeOH (19:1))and recrystallized from THF/diethyl ether/n-hexane to give 244 mg of acolorless needle crystal.

Melting point: 204.0°˜207.0° C.

Elemental analysis (C₂₁ H₁₅ NO₂ (MW=313.356)): Calcd.: C, 80.49; H, 4.83N, 4.47 Found: C, 80.64; H, 4.80; N, 4.51

IR (CHCl₃): 3445, 3185, 1763 (sh), 1747, 1668, 1600, 1519, 1486, 1449,1407 cm⁻¹

NMR (CDCl₃): δ 7.29˜7.50 (m, 6H), 7.50˜7.65 (m, 8H), 10.190 (brs, 1H)

EXAMPLE 117

5-(4-Biphenyl)-3-benzyl-4-phenyloxazolin-2-one (I-35) (0089)

To a solution of oxazoline (compound 0088) (1.071 g, 3.30 mmol) producedin Example 116 in DMF (10 ml), NaH (60%, 145 mg, 3.63 mmol) and benzylbromide (1.18 ml, 9.91 mmol) were added, and the mixture was stirred for2.5 hours with ice cooling. The reaction solution was poured into icewater and the solution was extracted with ethyl acetate. The ethylacetate layer was washed with water and dried, and then the solvent wasdistilled off under reduced pressure to give 2.264 g of a yellow oilyproduct, which was purified by silica gel chromatography (SiO₂ 124 g;eluted with toluene˜toluene/acetone (19:1)) and recrystallized from EtOHto give 912 mg of a colorless needle crystal (68.4%).

Melting point: 111.5°˜112.5° C.

Elemental analysis (C₂₈ H₂₁ NO₂ (MW=403.481)): Calcd.:C, 83.35; H, 5.25;N, 3.47 Found: C, 83.33; H, 5.13; N, 3.50

IR (CHCl₃): 1749, 1601, 1520, 1497, 1489, 1457, 1448, 1435, 1410, 1386cm⁻¹

NMR (CDCl₃): δ 4.682 (s, 2H), 6.94˜7.08 (m, 2H), 7.16˜7.62 (m, 17H)

EXAMPLE 118

4-(4-Biphenyl)-5-phenyl-oxazolin-2-one (I-42) (0144)

(1) Methyl 2-(4-biphenyl)-2,3-epoxy-3-phenyl propionate (I-39)

To a solution of bromo acetate (I-38) (3.47 g, 11.37 mmol) in MeOH (62ml), Na (282 mg, 12.28 mmol) and benzaldehyde (1.16 ml, 11.37 mmol) wereadded, and the mixture was stirred at room temperature for 4 hours. Thesolution of benzaldehyde (0.58 ml, 5.69 mmol) and Na (136 mg, 5.91 mmol)in MeOH (7 ml) was further added, and the mixture was stirred at roomtemperature overnight. The reaction solution was poured into ice waterand crystal precipitated was filtered. The crystal was dissolved in CH₂Cl₂ and dried, then the solvent was distilled off under reducedpressure. The residue was purified by silica gel chromatography (SiO₂217 g; eluted with toluene), and then recrystallized from CH₂ Cl₂ /Et₂O/n-hexane to give 2.64 g of a colorless columnar crystal (70.2%), m.p.128.5˜130.0° C.

Elemental analysis (C₂₂ H₁₈ O₃ (MW=330.383)): Calcd. C, 79.98; H, 5.49Found C, 79.80; H, 5.62

IR (CHCl₃): 1738, 1600, 1488, 1451, 1448, 1437, 1397 cm⁻¹

NMR (CDCl₃): δ 3.827 (s, 3H), 4.597 (s, 1H), 6.97˜7.22 (m, 5H),7.26˜7.60 (m, 9H)

(2) Sodium 2-(4-biphenyl)-2,3-epoxy-3 phenylpropionate (I-40)

Methyl ester (I-39) (2.59 g, 7.84 mmol) was dissolved in a solution ofan aqueous 1N-NaOH solution (8.2 ml, 8.23 mmol) in MeOH (37 ml)/THF (24ml), and the mixture was stirred for 10 minutes with ice cooling, andstirred at room temperature for 3 hours. The solvent of the reactionsolution was distilled off under reduced pressure. The residue waswashed with Et₂ O to give 2.66 g of a colorless crystal (quantitative).

Melting point: >300 ° C.

Elemental analysis (C₂₁ H₁₅ O₃ Na0.3H₂ O (MW=343.743)): Calcd. C, 73.38;H, 4.57; Na, 6.69 Found C, 73.23; H, 4.49; Na, 7.07

IR (nujol): 3040, 1622, 1489, 1457, 1386cm⁻¹

NMR (d₆ -DMSO): δ 4.340 (s, 1H), 6.96˜7.19 (m, 5H), 7.24˜7.51 (m, 7H),7.51˜7.60 (m, 2H)

(3) Titled compound 0144

To a solution of a Na salt (I-40) (2.58 g, 7.62 mmol) in THF (38 ml),oxalyl chloride (13.6 ml, 152 mmol) was dropwise added with ice cooling,and the mixture was stirred at the same temperature for 30 minutes.After stirring at room temperature for additional 1.5 hours, the solventwas distilled off under reduced pressure. After the resulting residuewas dissolved in THF (38 ml), Me₃ SiN₃ (5.32 ml, 38.1 mmol) was added,and the mixture was heated under reflux for 4 hours. The solvent of thereaction solution was distilled off under reduced pressure and theresidue was dissolved in CHCl₃ /MeOH (9:1). After the solution waswashed with water and dried, the solvent was distilled off. Theresulting crystalline residue of cream color was recrystallized fromTHF/Et₂ O to give 1.362 g of a colorless needless crystal.

Melting point: 201.0°˜204.0° C.

Elemental analysis (C₂₁ H₁₅ NO₂ (MW=313.356)): Calcd.: C, 80.49; H,4.83; N, 4.47 Found: C, 80.44; H, 4.99; N, 4.57

IR (CHCl₃): 3463, 3190, 2335, 1765 (sh), 1748, 1676, 1600, 1498, 1489,1449 cm⁻¹

NMR (CDCl₃): δ 7.27˜7.72 (m, 14H), 10.316 (brs, 1H)

EXAMPLE 119

4-(4-Biphenyl)-3-benzine-5-phenyl-oxazolin-2-one (I-43) (0145)

To a solution of oxazoline (1.02 g, 3.17 mmol) produced in Example 118in DMF (10 ml), NaH (60%, 140 mg, 3.49 mmol) and benzyl bromide (1.13ml, 9.51 mmol) were added, and the mixture was stirred for 2.5 hourswith ice cooling. The reaction solution was poured into ice water andthe solution was extracted with EtOAc. The EtOAc layer was washed withwater and dried, and the solvent was distilled off under reducedpressure to give 2.17 g of a yellow oily product, which was purified bysilica gel chromatography (SiO₂ 138 g; eluted with toluene andtoluene/EtOAc (19:1)) to give 1.02 g of an oily residue of cream color(80%).

Elemental analysis (C₂₈ N₂₁ NO₂ (MW=403.481)): Calcd. C, 83.35; H, 5.25;N, 3.47 Found: C, 83.33; H, 5.13; N, 3.50

IR (CHCl₃): 1748, 1660, 1600, 1498, 1488, 1448, 1435, 1381 cm⁻¹

NMR (CDCl₃): δ 4.701 (s, 2H), 6.98˜7.11 (m, 2H), 7.14˜7.56 (m, 13H),7.58˜7.72 (m, 4H)

EXAMPLE 120

Compound 0093 ##STR137##

According to the method similar to that described in Example 110, anoxazoline derivative was obtained and the oxazoline derivative wasbenzylated according to the method similar to that described in Example15 to give the titled compound. oily substance

IR: (CHCl₃): 1745, 1610, 1513 cm⁻¹.

Mass m/z 477 (M⁺)

EXAMPLE 121

4,5-Diphenyl-3-N-phenylethyl-3-oxazolin-2-one (0075)

This compound was a known compound. ##STR138## Advantages

Arachidonic acid was a precursor of prostaglandins and leukotrieneswhich are inflamation inducers. Production of these inducers isinitiated by the action of phospholipase A₂ (PLA₂).

PLA₂ is a protein that hydrolyzes the 2-acyl ester bond ofphospholipids. Most familiar PLA₂ is Ca²⁺ -dependent secretory PLA₂.However, secretory PLA₂ does not selectively cleave phospholipidscontaining arachidonic acid, and therefore, it is thought to have littlesignificance in the initiation of prostaglandin and leukotrienebiosynthesis.

Recently, a novel type of PLA₂ found in cytosol was discovered invarious types of cells such as platelets, macrophages, interstitialcells of the renal glomeruli, monoblast and macrophage cell lines andkidney Clark, J. D. et al., Cell 65: 1043-1051, 1991!. This cytosolicPLA₂ (cPLA₂) preferentially hydrolyzes phospholipids containingarachidonic acid esterified in the 2-position Sharp, J. D. et al., J.Biol. Chem. 266: 14850-14853, 1991!. It is also thought that cPLA₂translocates to the cell membrane in response to physiological(cytosolic) increments in Ca²⁺ concentration and it is involved in theselective cleavage of arachidonic acid.

It is therefore expected that inhibition of this cytosolic PLA₂ activitymay lead to the inhibition of arachidonic acid liberation and hence tothe decreased production of prostaglandins and leukotrienes. Theinhibition of cytosolic PLA₂ is also considered to reduce the productionof platelet activating factor (PAF), one of the inflamation inducers.

Assay of cPLA₂ activity

Taking the above matter into consideration, the compounds of the presentinvention were evaluated for their effect on cytosolic PLA₂ activity asdescribed in published literature Kramer, R. M., Robers, E. F., Manetta,J. and Putanam, J. E. et al., J. Biol. Chem. 268 (8): 5268-5272, 1991!.Briefly, PLA₂ activity was assayed using sonicated liposomes containing1-palmitoyl-2- ¹⁴ C!arachidonyl-sn-glycero-3-phosphocholine andsn-1,2-dioleoyl glycerol at a molar ratio of 2:1. The assay mixturecontained 1 mM CaCl₂, 2 mM 2-mercaptoethanol, 150 mM NaCl, 50 mM Hepes,pH 7.4, and 0.1 mg/ml BSA. The substrate consisted of 2 μM radiolabeledphosphatidycholine liposomes containing 1 μM dioleoyl glycerol.

The amount of released fatty acids in the reaction as mentioned abovewas quantitated by a liquid scintillation counter. Separately, the sameassay was performed except that the compound of the present inventionwas not added to serve as the enzyme control. The inhibitioory activitywas expressed as a percent (%) of PLA₂ activity in the enzyme control,and thereby 50% inhibition concentration was calculated.

                  TABLE 11                                                        ______________________________________                                        Cytosolic PLA.sub.2 inhibition activity                                       Example No. (compound No.)                                                                    IC.sub.50 (μM)                                                                      % Inhibition at 2 μM                              ______________________________________                                        1        (0037)     207      None                                             15       (0067)     >50      None                                             16       (0071)     13       18%                                              17       (0070)     4.3      46%                                              18       (0069)     153      None                                             27       (0095)     35       26%                                              28       (0097)     28       48%                                              33       (0142)     220      None                                             34       (0153)     126      None                                             35       (0155)     57       None                                             36       (0156)     120      None                                             40       (0044)     54       19%                                              41       (0086)     8.3      19%                                              42       (0099)     42       12%                                              43       (0109)     250      None                                             51       (0039)     6.2      24%                                              52       (0047)     35       17%                                              53       (0048)     17       None                                             54       (0062)     50       None                                             55       (0090)     65       14%                                              56       (0091)     105      11%                                              62       (0054)     124      None                                             73       (0028)     103      None                                             75       (0073)     50       None                                             77       (0140)     89       None                                             81       (0029)     103      None                                             82       (0030)     103      None                                             84       (0079)     218      None                                             88       (0092)     8.3      28%                                              89       (0108)     59       None                                             92       (0212)     43       21%                                              93       (0168)     66       None                                             94       (0169)     85       None                                             95       (0181)     101      None                                             96       (0182)     66       None                                             97       (0199)     32       32%                                              98       (0213)     9.3      24%                                              99       (0246)     50       20%                                              100      (0247)     10       23%                                              101      (0288)     2.0      50%                                              102      (0289)     6.6      36%                                              103      (0296)     11       21%                                              104      (0313)     about 50 13%                                              105      (0315)     90       22%                                              106      (0325)     8.7      32%                                              107      (0346)     3.0      47%                                              108      (0347)     7.4      33%                                              109      (0303)     50       18%                                              121      (0075)     14       21%                                                       (0001)     6.0      34%                                                       (0002)     68       None                                             sample 1 (0003)     52       Nones                                            ______________________________________                                    

We claim:
 1. A compound represented by the formula: ##STR139## wherein aand b are each a carbon atom; a bond:- - - - between a and b indicatesthat it is a single bond or a double bond; X and Y independently are anoptionally substituted phenyl group; and Z is a C₃ -C₆ alkyl groupsubstituted by phenyl, an optionally substituted C₈ -C₁₅ alkenyl group,and an optionally substituted C₂ -C₇ alkynyl group.